Multifunctional quinoline derivatives as anti-neurodegenerative agents

ABSTRACT

Novel quinoline derivatives are disclosed. Also disclosed are synthesis and use thereof for treating neurodegenerative diseases.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 7,439,243 and 7,452,888 describe a series of quinolinederivatives useful for the treatment of CNS disorders, includingAlzheimer's disease. U.S. Pat. No. 7,009,053 describe a series ofquinoline derivatives useful for treatment of Alzheimer's disease,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, stroke, ischemia, traumatic brain injury, spinal cord injuryor osteoarthritis.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to a compound of Formula (I) or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof:

wherein

R¹ is hydrogen, (C₁-C₈)alkyl, (C₁-C₈)alkylene(C₃-C₈)cycloalkyl,(C₁-C₈)haloalkyl, or (C₁-C₈)alkylene(C₆C₂₀)aryl;

R² is a hydrogen or halogen;

R³ is hydrogen, halogen, (C₁-C₈)alkyl, or (C₁-C₈)alkoxy;

R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, or(C₁-C₈)haloalkyl;

R⁵ is hydrogen or (C₁-C₂₀)alkanol;

R⁶ is hydrogen; and

R⁷ is hydrogen, (C₁-C₂₀)alkanol, (C₁-C₈)alkylene(C₃-C₈)heterocyclyl(C₁-C₂₀)alkanol, (C₁-C₈)alkylene(C₃-C₈)heterocyclyl(C₁-C₂₀)alkyl,(C₁-C₈)alkylene(C₁-C₆)alkylamino(C₁-C₆)alkynyl,(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol, or(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol(C₁-C₈)alkylene substituted(C₃-C₂₀)heteroaryl.

In another aspect, the invention relates to a method for preparing thecompound as aforementioned, the method comprising:

(1) reacting the compound of Formula (II)

wherein:

R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or

R², R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or

R², R³, R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F, Cl,or Br; or

R², R⁵, R⁶ are each independently hydrogen, R³ OCH₃, and R⁴ is Cl; or

R², R⁴ is Cl and R³, R⁵, R⁶ are each independently hydrogen,

with benzyl bromide, methyl iodide, ethyl iodide, 2-bromopropane, ormethylenecyclopropyl bromide in a basic solution at about roomtemperature to about 80° C. to obtain the compound of Formula (III)

wherein:

R¹ is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or benzyl; and

R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or

R², R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or

R², R³, R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F, Cl,or Br; or

R², R⁵, R⁶ are each independently hydrogen, R³ is OCH₃, and R⁴ is Cl; or

R², R⁴ is Cl and R³, R⁵, R⁶ are each independently hydrogen;

(2) reacting the compound of Formula (III) with lithiumbis(trimethylsilyl)amide and a bromo(C₁-C₂₀)alkanol in tetrahydrofuranat 0° C. to obtain the compound of Formula (I)

wherein:

R¹ is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or benzyl;

R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or

R², R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or

R², R³, R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F, Cl,or Br; or

R², R⁵, R⁶ are each independently hydrogen, R³ is OCH₃, and R⁴ is Cl; orR³ is Cl, and R⁴ is OCH₃ or

R², R⁴ is Cl and R³, R⁵, R⁶ are each independently hydrogen; and

R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH,

(3) reacting the compound of Formula (I), wherein R¹ is benzyl, withhydrogen gas under pressure with palladium on carbon at room temperaturein methanol or with boron trichloride in dichloromethane at 0° C. toobtain the compound of Formula (I)

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or

R¹, R², R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or

R¹, R², R³, R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F,Cl, or Br; or

R¹, R², R⁵, R⁶ are each independently hydrogen, R³ is OCH₃, and R⁴ isCl; or

R², R⁴ is Cl and R¹, R³, R⁵, R⁶ are each independently hydrogen; and

R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH;or

(4) reacting the compound of Formula (I), wherein R¹, R², R³, R⁴, R⁵,and R⁶ are each independently hydrogen and R⁷ is (CH₂)₁₁OH, withN-chlorosuccinimide in methylene chloride at room temperature to affordthe compound of Formula (I), wherein R¹, R³, R⁵, and R⁶ are eachindependently hydrogen, R² and R⁴ are each independently chlorine, andR⁷ (CH₂)₁₁OH; or

(5) reacting the compound of Formula (I), wherein R¹ is methyl, R², R³,R⁴, R⁵, and R⁶ are each independently hydrogen and R⁷ is (CH₂)₁₁OH,(CH₂)₁₂OH or (CH₂)₁₃OH with concentrated hydrochloric acid, ICl₃, andglacial acetic acid to afford the compound of Formula (I), wherein R¹ ismethyl R², R³, R⁵, and R⁶ are each independently hydrogen, R⁴ is Cl, andR⁷ is (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH,(CH₂)₁₀OCOCH₃, (CH₂)₁₁OCOCH₃, (CH₂)₁₂OCOCH₃, (CH₂)₁₃OCOCH₃; or

(6) reacting 2-aminophenol with methylvinyl ketone in hydrochloric acidto obtain the compound of Formula (INT-1),

(7) reacting the compound of Formula (INT-1) with methyl iodide, ethyliodide, 2-bromopropane, methylenecyclopropyl bromide, or benzyl bromidein basic solution to afford the compound of Formula (III),

wherein R¹⁰ is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl;

(8) reacting the compound of Formula (III), wherein R¹⁰ is methyl,ethyl, 2-propyl, methylenecyclopropyl, or benzyl, with lithiumbis(trimethylsilyl)amide and 10-bromo-1-decanol or 11-bromo-1-undecanolin tetrahydrofuran at 0° C. to obtain the compound of Formula (I),wherein R¹ is methyl, ethyl, 2-propyl, methylenecyclopropyl or benzyl;R², R³, R⁴, R⁶, and R⁷ are each independently hydrogen; and R⁵ is(CH₂)₁₁OH or (CH₂)₁₂OH;

(9) reacting the compound of Formula (I), wherein R¹ is benzyl; R², R³,R⁴, R⁶, and R⁷ are each independently hydrogen; and R⁵ is (CH₂)₁₁OH or(CH₂)₁₂OH, with hydrogen gas under pressure with palladium on carbon atroom temperature in methanol to obtain the compound of Formula (I),wherein R¹ is hydrogen; R², R³, R⁴, R⁶, and R⁷ are each independentlyhydrogen; and R⁵ is (CH₂)₁₁OH or (CH₂)₁₂OH; or

(10) reacting 2-trifluoromethoxyanaline with crotonaldehyde to obtain2-methyl-8-trifluormethoxyquinoline, which is treated with lithiumbis(trimethylsilyl)amide and a bromo(C₁C₂₀)alkanol in tetrahydrofuran at0° C. to obtain the compound of Formula (I), wherein R¹ istrifluoroemethyl; R², R³, R⁴, R⁵, and R⁷ are each independentlyhydrogen; and R⁷ is (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, or(CH₂)₁₅OH; or

(11) reacting an 8-hydroxy-2-methylquinoline compound of Formula (IV),wherein R¹ is hydrogen, methyl, ethyl 2-propyl, or methylenecyclopropyl,

with selenium dioxide in dioxide at elevated temperature to afford acompound of Formula (VI), R¹ is hydrogen, methyl, ethyl, 2-propyl, ormethylenecyclopropyl.

(12) reacting the compound of Formula (VI), wherein R¹ is hydrogen,methyl, ethyl, 2-propyl, or methylenecyclopropyl, withN-methylpropagylamine to obtain a compound of Formula (I), wherein R¹ ishydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂, R², R³,R⁴, R⁵, and R⁶ are each independently hydrogen; and R⁷ isCH₂N(CH₃)CH₂C≡CH; or

(13) reacting the compound of Formula (VI), R¹ is hydrogen, methyl,ethyl, 2-propyl, or methylenecyclopropyl, with 2(piperazin-1-yl) ethanolto obtain a compound of Formula (I), wherein R¹ is hydrogen, CH₃,CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂, R², R³, R⁴, R⁵, and R⁶are each independently hydrogen; and R⁷ is CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH; or

(14) reacting compound of Formula (VI) with an amino(C₁-C₂₀)alkanol toobtain a compound of Formula (I), wherein R¹ is hydrogen, CH₃, CH₂CH₃,CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂; R², R³, R⁴, R⁵, and R⁶ are eachindependently hydrogen; and R⁷ is CH₂NH(CH₂)₈OH, orCH₂N((CH₂)₆OH)CH₂(8-methoxyquinolin-2-yl).

In another aspect, the invention relates to a composition comprising atherapeutically effective amount of the compound as aforementioned, or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof, and a pharmaceutically acceptable diluent orcarrier.

In another aspect, the invention relates to a method of treating aneurodegenerative disease, comprising administering to a subject in needthereof a therapeutically effective amount of a compound asaforementioned, or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable vehicle or carrier.

Further in another aspect, the invention relates to a compositioncomprising a compound as aforementioned, or a pharmaceuticallyacceptable salt, a solvate or hydrate, a prodrug, or a metabolitethereof, and a pharmaceutically acceptable diluent or carrier for use intreating a neurodegenerative disease.

Yet in another aspect, the invention relates to a use of a compound asaforementioned in the manufacture of a medicament for treating aneurodegenerative disease. In one embodiment, the medicament is fortreating Alzheimer's disease.

These and other aspects will become apparent from the followingdescription of the preferred embodiment taken in conjunction with thefollowing drawings, although variations and modifications therein may beaffected without departing from the spirit and scope of the novelconcepts of the disclosure.

The accompanying drawings illustrate one or more embodiments of theinvention and, together with the written description, serve to explainthe principles of the invention. Wherever possible, the same referencenumbers are used throughout the drawings to refer to the same or likeelements of an embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-B show morphological analysis of the effects of compound C12 onfAβ formation and dissociation of fAβs in the presence or absence ofzinc ions.

FIG. 2 shows compound C12 inhibiting polymerization of Aβ in the absenceof zinc ions.

FIGS. 3A-B show compound C12 acting as a neuroprotective agent targetingfAβ.

FIG. 4 shows quinoline derivatives-induced neurite outgrowth.

FIG. 5 shows quinoline derivatives increased expression of GAP43 (amarker for neurite outgrowth).

FIG. 6 shows the results of rotarod test.

FIGS. 7A-D show the results of Morris water maze test.

FIG. 8 shows an increase in GAP43 level and decrease in fAβ level inmemory-deficit fAβ-lesioned mice after compound C12 treatment.

DETAILED DESCRIPTION OF THE INVENTION

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,the moiety —CONH₂ is attached through the carbon atom

The term “amino” refers to —NH₂. The amino group can be optionallysubstituted as defined herein for the term “substituted.” The term“alkylamino” refers to —NR₂, wherein at least one R is alkyl and thesecond R is alkyl or hydrogen. The term “acylamino” refers to N(R)C(50O)R, wherein each R is independently hydrogen, alkyl, or aryl.

The term “alkyl” refers to a C₁-C₁₈ hydrocarbon containing normal,secondary, tertiary or cyclic carbon atoms. Examples are methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl (iso-butyl,—CH₂CH(CH₃)₂), 2-butyl (sec-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl(tert-butyl, —C(CH₃)₃), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl. The alkyl can be a monovalent hydrocarbon radicalas described and exemplified above, or it can be a divalent hydrocarbonradical (i.e., alkylene). The alkyl can optionally be substituted withone or more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl or hydroxy. The alkyl can optionally be interrupted with oneor more non-peroxide oxy (—O—), thio (—S—), imino (—N(H)—), methylenedioxy (—OCH₂O—), carbonyl (—C(═O)—), carboxy (—C(═O)—), carbonyldioxy(—OC(═O)O—), carboxylato (—OC(═O)—), imino (C═NH), sulfinyl (SO) orsulfonyl (SO₂). Additionally, the alkyl can optionally be at leastpartially unsaturated, thereby providing an alkenyl.

The term, “alkylene” refers to a saturated, branched or straight chainor cyclic hydrocarbon radical of 1-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or different carbon atoms of a parent alkane. Typicalalkylene radicals include, but are not limited to: methylene (—CH₂—)1,2-ethylene (—CH₂CH₂—), 1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene(—CH₂CH₂CH₂CH₂—), and the like. The alkylene can optionally besubstituted with one or more alkoxy, halo, haloalkyl, hydroxy,hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro,trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy,acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl or hydroxy. Additionally, the alkylene can optionally beinterrupted with one or more non-peroxide oxy (—O—), thio (—S—), imino(—N(H)—), methylene dioxy (—OCH₂O—), carbonyl (—C(═O)—), carboxy(—C(═O)O—) carbonyldioxy (—OC(═O)O—), carboxylato (—OC(═O)—), imine(C═NH), sulfinyl (SO) or sulfonyl (SO₂). Moreover, the alkylene canoptionally be at least partially unsaturated, thereby providing analkenylene.

The term “alkynyl” refers to a monoradical branched or unbranchedhydrocarbon chain, having a point of complete unsaturated (i.e., acarbon-carbon, sp triple bond). In one embodiment, the alkynyl group canhave from 2 to 10 carbon atoms, or 2 to 6 carbon atoms. In anotherembodiment, the alkynyl group can have from 2 to 4 carbon atoms. Thisterm is exemplified by groups such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,1-octynyl and the like. The alkynyl can be unsubstituted or substituted.

The term “alkoxy” refers to the group alkyl-O—, where alkyl is definedherein. Preferred alkoxy groups include, e.g., methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, 1,2-dimethylbutoxy, and the like. The alkoxy can optionally besubstituted with one or more halo, haloalkyl, hydroxy, hydroxyalkyl,aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl,amino, imino, alkylamino, acylamino, nitro, trifluoromethyl,trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl,benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The term “alkanol” refers to a compound of a general formula ROH, whereR is alkyl, as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings, wherein at least one ring is aromatic(e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferredaryls include phenyl, naphthyl and the like. The aryl can optionally bea divalent radical, thereby providing an arylene. The aryl canoptionally be substituted with one or more alkyl alkenyl, alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle,cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino,acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy,carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl,cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl,sulfino, sulfo, sulfoamino, thiosulfo, NR^(x)R^(y) and/or COOR^(x),wherein each R^(x) and R^(y) are independently H, alkyl, alkenyl, aryl,heteroaryl, heterocycle, cycloalkyl, or hydroxy.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

The term “carbocycle” refers to a saturated, unsaturated or aromaticring having 3 to 8 carbon atoms as a monocyclic, 7 to 12 carbon atoms asa bicycle, and up to about 30 carbon atoms as a poly cycle. Monocycliccarbocycles typically have 3 to 6 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples ofcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryland naphthyl. The carbocycle can be optionally substituted as describedabove for alkyl groups.

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other by achemically feasible bonding configuration.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.The cycloalkyl can optionally be substituted with one or more alkyl,alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy. The cycloalkyl can optionally be at leastpartially unsaturated, thereby providing a cycloalkenyl. Additionally,the cycloalkyl can optionally be a divalent radical, thereby providing acycloalkylene.

The term “an effective amount” refers to an amount sufficient to effectbeneficial or desired results. Determination of an effective amount fora given administration is well within the ordinary skill in thepharmaceutical arts.

The term “halo” refers to fluoro, chloro, bromo, and iodo. Similarly,the term “halogen” refers to fluorine, chlorine, bromine, and iodine.

The term “haloalkyl” refers to alkyl substituted by 1-4 halo groups,which may be the same or different. Representative haloalkyl groupsinclude trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” is a monocyclic, bicyclic, or tricyclic ringsystem containing one, two, or three aromatic rings and containing atleast one nitrogen, oxygen, or sulfur atom in an aromatic ring, andwhich can be unsubstituted or substituted. The heteroaryl can optionallybe a divalent radical, thereby providing a heteroarylene. Examples ofheteroaryl groups include, but are not limited to, 2H-pyrrolyl,3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl, acridinyl, benzo[b]thienyl,benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl,dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl,indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindoyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-b],oxazolyl, perimidinyl, phenathridinyl, phenanthrolinyl, phenarsazinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl,and xanthenyl. In one embodiment the term “heteroaryl” denotes amonocyclic aromatic ring containing five or six ring atoms containingcarbon and 1, 2, 3, or 4 heteroatoms independently selected from thegroup non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H,O, alkyl phenyl, or benzyl. In another embodiment heteroaryl denotes anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, or tetramethylene diradical thereto.

The heteroaryl can optionally be substituted with one or more alkylalkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino,imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

The term “heterocycle” or “heterocyclyl” refers to a saturated orpartially unsaturated ring system, containing at least one heteroatomselected from the group oxygen, nitrogen, and sulfur, and optionallysubstituted with alkyl, or C(—O)OR^(b), wherein R^(b) is hydrogen oralkyl. Typically heterocycle is a monocyclic, bicyclic, or tricyclicgroup containing one or more heteroatoms selected from the group oxygen,nitrogen, and sulfur. A heterocycle group also can contain an oxo group(═O) attached to the ring. Non-limiting examples of heterocycle groupsinclude 1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane,2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl,imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine,piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl,pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine.The heterocycle can optionally be a divalent radical, thereby providinga heterocyclene. The heterocycle can optionally be substituted with oneor more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl,aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl,amino, imino, alkylamino, acylamino, nitro, trifluoromethyl,trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl,benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pynmidine,pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

The term “hydrate” refers to the complex where the solvent molecule iswater.

The terms “individual,” “host,” “subject,” and “patient” are usedinterchangeably, and refer to a mammal, including, but not limited to,primates, including simians and humans.

The term “metabolite” refers to any compound of the Formula (I) producedin vivo or in vitro from the parent drug, or its prodrugs.

The pharmaceutically acceptable salts of the compounds described hereincan be synthesized from the parent compound, which contains a basic oracidic moiety, by conventional chemical methods. Generally, such saltscan be prepared by reacting the free acid or base forms of thesecompounds with a stoichiometric amount of the appropriate base or acidin water or in an organic solvent, or in a mixture of the two:generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol, or acetonitrile are preferred. Lists of many suitable saltsare found in Remington: The Science and Practice of Pharmacy, 21^(st)edition, Lippincott Williams & Wilkins, (2005).

Pharmaceutically acceptable prodrugs refer to a compound that ismetabolized, for example hydrolyzed or oxidized, in the host to form acompound of the Formula (I). Typical examples of prodrugs includecompounds that have biologically labile protecting groups on afunctional moiety of the active compound. Prodrugs include compoundsthat can be oxidized, reduced, animated, deaminated, hydroxylated,dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,acylated, deacylated, phosphorylated, dephosphorylated to produce theactive compound.

The prodrug can be readily prepared from the compounds of Formula (I)using methods known in the art. See, e.g. See Notari, R. E., “Theory andPractice of Prodrug Kinetics,” Methods in Enzymology, 112:309 323(1985); Bodor, N., “Novel Approaches in Prodrug Design,” Drugs of theFuture, 6(3): 165 182 (1981); and Bundgaard, H., “Design of Prodrugs:Bioreversible-Derivatives for Various Functional Groups and ChemicalEntities,” in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y.(1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol.1, pp. 172 178, 949 982(1995).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute (in this invention, a compound of Formula I, or a salt orphysiologically functional derivative thereof) and a solvent. Suchsolvents, for the purpose of the invention, should not interfere withthe biological activity of the solute. Non-limiting examples of suitablesolvents include, but are not limited to water, methanol, ethanol, andacetic acid. Preferably the solvent used is a pharmaceuticallyacceptable solvent. Non-limiting examples of suitable pharmaceuticallyacceptable solvents include water, ethanol, and acetic acid.

The phrase “room temperature” refers to a temperature in the range ofabout 20° C. to about 30° C.

The term “substituted” is intended to indicate that one or morehydrogens on the atom indicated is replaced with a selection from theindicated group(s), provided that the indicated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.Suitable indicated groups include, e.g., alkyl, alkenyl, alkylidenyl,alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,heteroaryl, heterocycle, cycloalkyl, alkanoyl, acyloxy, alkoxycarbonyl,amino, imino, alkylamino, acylamino, nitro, trifluoromethyl,trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio,alkylsulfonyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl,benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,isocyanato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,thiosulfo, NR^(x)R^(y) and/or COOR^(x), wherein each R^(x) and R^(y) areindependently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,cycloalkyl, or hydroxy. When a substituent is oxo (i.e., ═O) or thioxo(i.e., ═S) group, then two hydrogens on the atom are replaced.

The terms “treating” or “treat” or “treatment” refer to obtaining adesired pharmacologic and/or physiologic effect. The effect may beprophylactic in terms of completely or partially preventing a disease orsymptom thereof and/or may be therapeutic in terns of a partial orcomplete cure for a disease and/or adverse affect attributable to thedisease.

The invention relates to multifunctional quinoline derivatives havingfollowing properties: metal chelation, clearance of reactive oxygenspecies, anti-aggregation, neurite outgrowth and neuron proliferation.They are useful for treating neurodegenerative disease involvingneuronal toxicity or dysfunction induced by oxidative stress and otherdisorders associated with misfolding protein aggregation. In animalmodel, quinoline derivatives (B3 or C12) at 1 to 100 mg/kg, preferable 1to 10 mg/kg, i.p. daily) were found to improve memory of mice withoutcausing significant toxicity.

In one aspect, the invention relates to a compound of Formula (I) or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof:

wherein

R¹ is hydrogen, (C₁-C₈)alkyl, (C₁-C₈)alkylene(C₃-C₈)cycloalkyl,(C₁-C₈)haloalkyl, or (C₁-C₈)alkylene(C₆-C₂₀)aryl;

R² is hydrogen or halogen;

R³ is hydrogen, halogen, (C₁-C₈)alkyl, or (C₁-C₈)alkoxy;

R⁴ is hydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, or(C₁-C₈)haloalkyl;

R⁵ is hydrogen (C₁-C₂₀)alkanol;

R⁶ is hydrogen; and

R⁷ is hydrogen, (C₁-C₂₀)alkanol, (C₁-C₈)alkylene(C₃-C₈)heterocycly(C₁-C₂₀)alkanol, (C₁-C₈)alkylene(C₃-C₈)heterocyclyl(C₁-C₂₀)alkyl,(C₁-C₈)alkylene(C₁-C₆)alkylamino(C₁-C₆)alkynyl,(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol, or(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol(C₁-C₈)alkylene substituted(C₃-C₂₀)heteroaryl.

In one embodiment of the invention, wherein

R¹ is hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CF₃, or benzyl;

R² is hydrogen, F, or Cl;

R³ is hydrogen, F, Cl, CH₃, or OCH₃;

R⁴ is hydrogen, F, Cl, Br, CH₃, OCH₃, or CF₃;

R⁵ is hydrogen, (CH₂)₁₁OH, or (CH₂)₁₂OH;

R⁶ is hydrogen; and

R⁷ is hydrogen, (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH,(CH₂)₁₄OH, (CH₂)₁₅OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₃,CH₂N(CH₃)CH₂C≡CH, CH₂NH(CH₂)₈OH, orCH₂N((CH₂)₆OH)CH₂(8-methoxyquinolin-2-yl).

In another embodiment of the invention, wherein

R¹ is hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, CF₃, orbenzyl;

R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; and

R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₄OH,(CH₂)₁₅OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH, or CH₂N(CH₃)CH₂C≡CH.

In another embodiment of the invention, wherein

R¹is hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂;

R², R³, R⁵, and R⁶ are each independently hydrogen;

R⁴ is CH₃, F, Cl, Br, CF₃, or OCH₃; and

R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH,(CH₂)₁₀OCOCH₃, (CH₂)₁₁OCOCH₃, (CH₂)₁₂OCOCH₃, (CH₂)₁₃OCOCH₃,CH₂NH(CH₂)₈OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₃, orCH₂N(CH₃)CH₂C≡CH.

In another embodiment of the invention, wherein

R¹ is hydrogen, CH₃, CH₂CH₃, CH(CH₂)₂, or CH₂CH(CH₂)₂;

R², R⁴ are each independently Cl;

R³, R⁵, and R⁶ are each independently hydrogen; and

R⁷ is (CH₂)₁₁OH, CH₂NH(CH₂)₈OH, or CH₂N(CH₃)CH₂C≡CH.

In another embodiment of the invention, wherein

R¹ is hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, CH(CH₃)₂, orbenzyl;

R², R³, R⁴, R⁶, and R⁷ are each independently hydrogen; and

R⁵ is (CH₂)₁₁OH or (CH₂)₁₂OH.

In another embodiment of the invention, wherein

R¹ is CH₃;

R², R⁵, and R⁶ are each independently hydrogen;

R³ and R4 are each independently OCH₃or Cl; and

R⁷ is (CH₂)₁₁OH.

In another embodiment of the invention, the compound is selected fromthe group consisting of 9-(8-(benzyloxy)quinolin-2-yl)nonan-1-ol,10-(8-(benzyloxy)quinolin-2-yl)decan-1-ol,11-(8-(benzyloxy)quinolin-2-yl)undecan-1-ol,12-(8-(benzyloxy)quinolin-2-yl)dodecan-1-ol,13-(8-(benzyloxy)quinolin-2-yl)tridecan-1-ol,14-((8-(benzyloxy)quinolin-2-yl)tetradecan-1-ol,15-(8-(benzyloxy)quinolin-2-yl)pentadecan-1-ol,11-(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-5-fluoroquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-1-ol,2-(9-hydroxynonyl)quinolin-8-ol, 2-(10-hydroxydecyl)quinolin-8-ol,2-(11-hydroxyundecyl)quinolin-8-ol, 2-(12-hydroxydodecyl)quinolin-8-ol,2-(13-hydroxytridecyl)quinolin-8-ol,2-(14-(-hydroxytetradecyl)quinolin-8-ol,2-(15-hydroxypentadecyl)quinolin-8-ol,2-(11-hydroxyundecyl)-5-methylquinolin-8-ol,2-(11-hydroxyundecyl)-6-methylquinolin-8-ol,5-chloro-2-(11-hydroxyundecyl)quinolin-8-ol,9-(8-methoxyquinolin-2-yl)nonan-1-ol,10-(8-methoxyquinolin-2-yl)decan-1-ol,11-(8-methoxyquinolin-2-yl)undecan-1-ol,12-(8-methoxyquinolin-2-yl)dodecan-1-ol,13-(8-methoxyquinolin-2-yl)tridecan-1-ol,14-((8-methoxyquinolin-2-yl)tetradecan-1-ol,15-(8-methoxyquinolin-2-yl)pentadecan-1-ol,11-(8-methoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(5-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-1-ol,9-(5-chloro-8-methoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-methoxyquinolin-2-yl)undecan-1-ol,11-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-ol,11-(5,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(8-methoxy-6-methylquinolin-2-yl)undecan-1-ol,11-(6-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(6-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(7-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(7-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-1-ol,9-(8-ethoxyquinolin-2-yl)nonan-1-ol,10-(8-ethoxyquinolin-2-yl)decan-1-ol,11-(8-ethoxyquinolin-2-yl)undecan-1-ol,12-(8-ethoxyquinolin-2-yl)dodecan-1-ol,13-(8-ethoxyquinolin-2-yl)tridecan-1-ol,14-((8-ethoxyquinolin-2-yl)tetradecan-1-ol,15-(8-ethoxyquinolin-2-yl)pentadecan-1-ol,11-(8-ethoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-ethoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-ethoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-ethoxyquinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-1-ol,9-(8-isopropoxyquinolin-2-yl)nonan-1-ol,10-(8-isopropoxyquinolin-2-yl)decan-1-ol,11-(8-isopropoxyquinolin-2-yl)undecan-1-ol,12-(8-isopropoxyquinolin-2-yl)dodecan-1-ol,13-(8-isopropoxyquinolin-2-yl)tridecan-1-ol,14-((8-isopropoxyquinolin-2-yl)tetradecan-1-ol,15-(8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(8-isopropoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-isopropoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-1-ol,9-(8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol,10-(8-(cyclopropylmethoxy)quinolin-2-yl)decan-1-ol,11-(8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,12-(8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-1-ol,13-(8-cyclopropylmethoxy)quinolin-2-yl)tridecan-1-ol,14-((8-cyclopropylmethoxy)quinolin-2-yl)tetradecan-1-ol,15-(8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol,11-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-1-ol,11-(8(cyclopropylmethoxy)-5-fluoroquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol,11-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,5,7-dichloro-2-(11-hydroxyundecyl)quinolin-8-ol,10-(5-chloro-8-methoxyquinolin-2-yl)decan-1-ol, acetic acid10-(5-chloro-8-methoxyquinolin-2-yl)decyl ester,11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1-ol, acetic acid11-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester,12(5-chloro-8-methoxyquinolin-2-yl)dodecan-1-ol, acetic acid12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester,13-(5-chloro-8-methoxyquinolin-2-yl)tridecan-1-ol, acetic acid13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester,11-(8-methoxyquinolin-4-(-yl)undecan-1-ol,11-(8-ethoxyquinolin-4-(-yl)undecan-1-ol,11-(8-isopropoxyquinolin-4-(-yl)undecan-1-ol,11-(8-(cyclopropylmethoxy)quinolin-4-(-yl)undecan-1-ol,11-(8-(benzyloxy)quinolin-4-(-yl)undecan-1-ol,12-(8-(benzyloxy)quinolin-4-(-yl)dodecan-1-ol,4-((11-hydroxyundecyl)quinolin-8-ol,4-((12-hydroxydodecyl)quinolin-8-ol,9-(8-(trifluoromethoxy)quinolin-2-yl)nona-1-ol,11-(8-(trifluoromethoxy)quinolin-2-yl)undecan-1-ol,14-((8-(trifluoromethoxy)quinolin-2-yl)tetradecan-1-ol,15-(8-trifluoromethoxy)quinolin-2-yl)pentadecan-1-ol,2-((4-((2-hydroxyethyl)piperazine-1-yl)methyl)quinolin-8-ol,2-(4-(((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazine-1-yl)ethanol,2-(4-(((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazine-1-yl)ethanol,2-(4-(((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-(4-(((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethane,2-(4-(((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazine-1-yl)ethanol,2-(4-(((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol,5-chloro-2((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol,N((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1amine,N((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2yn-1-amine,N((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methoxyprop-2-yn-1-amine,8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-ol,8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-ol,and 6-(bis((8-methoxyquinolin-2-yl)methyl)amino)hexan-1-ol.

In another aspect, the invention relates to a composition comprising acompound as aforementioned, or a pharmaceutically, acceptable salt, asolvate or hydrate, a prodrug, or a metabolite thereof and apharmaceutically acceptable diluent or carrier for use in treating aneurodegenerative disease.

In one embodiment of the invention, the neurodegenerative disease isselected from the group consisting of Alzheimer's disease, amyotrophiclateral sclerosis (ALS), cataract, cognitive disorder, cerebralischaemia stroke, cerebral palsy, stroke, haemorrhagic stroke,Creutzfeldt-Jacob disease, spongiform encephalopathy, Mad Cow disease,dementia, depression, Down's syndrome, epilepsy, post-traumaticepilepsy, frontotemporal dementia, Gilles de la Tourette's syndrome,Hallerboden-Spatz disease, Huntington's disease, Lewy body disease,Parkinson's disease, cognitive impairment, learning deficit, maculardegeneration, memory deficit, multiple sclerosis, multiple systematrophy, motor neuron disease. Pick's disease, progressive supranuclearpalsy, pseudo dementia, retinopathy, senile dementia, schizophreniatransient anoxial induced neurodegeneration, pain, brain traumaticinjury, and spinal cord injury.

Chemistry Example 1—Preparation of (8-benzyloxyquinol-2-yl) and(8-hydroxyquinol-2-yl)alkyl alcohol

Reagents and conditions: (a) BnBr, KOH, EtOH, reflux, 15 h.; (b) 1)LHMDS, THF, 0° C., 1 h.; 2) Br(CH₂)_(n−1)OH, rt, 16-36 h.; (c) H₂, Pd/C,MeOH, rt, 6 to 10 h.; (d) BCl₃, CH₂Cl₂, 0° C. to rt, 3 h.

Method: The benzylation was performed as described by G. Serratrice etal. [Tetrahedron, 1996, 52, 4659-4672]. Benzyl bromide (6.45 g, 37.7mmol) was added to a stirred solution of 2-methylquinaldine (5.0 g, 31.4mmol) and KOH (1.95 g, 34.8 mmol) in 60 ml EtOH under reflux condition.After 15 h, the reaction mixture was filtered and filtrate removed invacuo. The residue was purified by flash column chromatography withHex/EA (6:1) and recrystallized in Hexane to give intermediate. LHMDS(2.2 to 2.5 equiv.) was treated with a stirred solution of (1 equiv.) in20 ml THF at 0° C. for 1 h. Corresponding Br(CH₂)_(n−1)OH (1.0 to 1.2equiv.) was added to a reaction mixture and the temperature wasrecovered to room temperature (RT) for further 15 to 36 h. The solventwas removed under a reduced pressure. The brown oily residue waspurified by flash column chromatography with Hex/EA (3:1 to 2:1) orDCM/EA (15:1 to 9:1) and recrystallized by Hexane/EA to afford series ofcompounds A. Removal of benzyl group of series of compounds A wascarried out in the presence of 10% Pd/C under hydrogen at RT for 6-10 h.The reaction mixture was filtered off and the filtrate purified by-flashcolumn chromatography by Hex/EA (4:1 to 3:1) to give series compound ofB. To a stirred solution of A11 (0.65 g, 1.4 mmol) in 20 ml CH₂Cl₂ wasadded 1M BCl₃ (2.8 ml, 2.8 mmol) at an ice bath for 3 h. The reactionmixture was poured into an ice bath and extracted by 50 ml CH₂Cl₂. Theorganic layer was concentrated in vacuum and residue purified by flashcolumn chromatography (EA) to afford the product (0.31 g, 60%).

9-(8-benzyloxy)quinolin-2-yl)nonan-1-ol (A1)

Yield (YD): 53%. ¹H NMR (400 MHz, d4-MeOD) δ8.15 (d, J=8.4 Hz, 1H), 7.52(d, J=6.8 Hz, 2H), 7.31˜7.41 (m, 5H), 7.29 (d, J=2.0 Hz, 1H), 7.15 (dd,J=7.6, 2.0 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.00 (t, J=8.0Hz, 2H), 1.80 (quin, J=6.8 Hz, 2H), 1.50 (t, J=7.2 Hz, 2H), 1.28-1.42(br, 11H); MS. m/z 400.0, [M+Na]⁺.

10-(8-benzyloxy)quinolin-2-yl)decan-1-ol (A2)

YD: 41%. ¹H NMR (400 MHz, d4-MeOD) δ8.14 (d, J=8.4 Hz, 1H), 7.52 (d,J=7.6 Hz, 2H), 7.32-7.42 (m, 5H), 7.28 (t, J=7.2 Hz, 1H), 7.14 (dd,J=7.6, 1.2 Hz, 1H), 5.38 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.98 (t, J=8.0Hz, 2H), 1.79 (quin, J=7.2 Hz, 2H), 1.49 (t, J=6.8 Hz, 2H), 1.29-1.40(br, 13H); MS. m/z 414.0, [M+Na]⁺.

11-(8-(benzyloxy)quinolin-2-yl)undecan-1-ol (A3)

YD: 42%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.4 Hz, 1H), 7.53 (d, J=7.2Hz, 2H), 7.27-7.39 (m, 6H), 7.02 (d, J=7.6 Hz, 1H), 5.46 (s, 2H), 3.63(t, J=6.8 Hz, 2H), 3.05 (t, J=8 Hz, 2H), 1.84 (q, J=7.6 Hz, 3H), 1.56(t, J=7.2 Hz, 2H), 1.29-1.46 (m, 12H); MS. m/z 428.3, [M+Na]⁺.

12-(8-(benzyloxy)quinolin-2-yl)dodecan-1-ol (A4)

YD: 44%. ¹H NMR (400 MHz, d4-MeOD) δ8.13 (d, J=8.4 Hz, 1H), 7.52 (d,J=7.6 Hz, 2H), 7.31-7.40 (m, 5H), 7.26 (d, J=7.6 Hz, 1H), 7.13 (dd,J=7.6, 0.8 Hz, 1H), 5.37 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.98 (t, J=7.6Hz, 2H), 1.78 (quin, 7.2 Hz, 2H), 1.49 (quin, J=7.2 Hz, 2H), 1.25-1.41(m, 17H); MS. m/z 442.3, [M+Na]⁺.

13-(8-(benzyloxy)quinolin-2-yl)tridecan-1-ol (A5)

YD: 40%. ¹H NMR (400 MHz, CDCl₃) δ7.95 (d, J=8.4 Hz, 1H), 7.45 (d, J=7.6Hz, 2H), 7.19-7.30 (m, 5H), 6.93 (d, J=7.6 Hz, 1H), 5.40 (s, 2H), 3.55(t, J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 1.77 (quin, J=7.6 Hz, 2H),1.46 (t, J=6.8 Hz, 2H), 1.19-1.38 (br, 19H); MS. m/z 456.3, [M+Na]⁺.

14-(8-benzyloxy)quinolin-2-yl)tetradecan-1-ol (A6)

YD: 51%. ¹H NMR (400 MHz, d4-MeOD) δ8.14 (d, J=8.4 Hz, 1H), 7.52 (d,J=7.2 Hz, 2H), 7.33-7.42 (m, 5H), 7.28 (t, J=7.2 Hz, 1H), 7.14 (d, J=6.8Hz, 1H), 5.38 (s, 2H), 3.52 (t, J=6.4 Hz, 2H), 2.98 (t, J=8.0 Hz, 2H),1.50 (quin, J=6.8 Hz, 2H), 1.47 (t, J=6.8 Hz, 2H), 1.22-1.4 (br, 21H);MS. m/z 447.3, [M+H]⁺.

15-(8-(benzyloxy)quinolin-2-yl)pentadecan-1-ol (A7)

YD: 42%. ¹H NMR (400 MHz, d4-MeOD) δ8.15 (d, J=8.4 Hz, 1H), 7.53 (d,J=7.2 Hz, 2H), 7.35-7.43 (m, 5H), 7.28-7.33 (m, 1H), 7.15 (dd, J=7.6,1.6 Hz, 1H), 5.39 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 2.99 (t, J=8.0 Hz,2H), 1.79 (quin, J=6.8 Hz, 2H), 1.51 (quin, J=6.8 Hz, 2H), 1.22-1.41(br, 23H); MS. m/z 462.3, [M+H]⁺.

11-(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-1-ol (A8)

YD: 47%. ¹H NMR (400 MHz, d4-MeOD) δ8.30 (d, J=8.4 Hz, 1H), 7.52 (d,J=7.2 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.26-7.36 (m, 3H), 7.17 (d, J=8.0Hz, 2H), 7.02 (d, J=8.0 Hz, 2H), 5.36 (s, 2H), 3.52 (t, J=6.4 Hz, 2H),3.00 (t, J=7.6 Hz, 2H), 2.55 (s, 3H), 1.80 (quin, J=7.2 Hz, 2H), 1.50(quin, J=6.8 Hz, 2H), 1.28-1.41 (m, 15H); MS. m/z 420.3, [M+H]⁺.

11-(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-1-ol (A9)

YD: 40%. ¹H NMR (400 MHz, d4-MeOD) δ8.03 (d, J=8.4 Hz, 1H), 7.53 (d,J=7.2 Hz, 2H), 7.33-7.37 (m, 3H), 7.26-7.30 (m, 1H), 7.16 (s, 1H), 7.00(d, J=1.2 Hz, 2H), 5.36 (s, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.95 (t, J=7.6Hz, 2H), 2.40 (s, 3H), 1.76 (q, J=7.6 Hz, 2H), 1.56 (t, J=7.2 Hz, 2H),1.29-1.46 (m, 15H); MS. m/z 442.3, [M+Na]⁺.

11-(8-benzyloxy)-5-fluoroquinolin-2-yl)undecan-1-ol (A10)

YD: 43%. ¹H NMR (400 MHz, CDCl₃) δ8.28 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.2Hz, 2H), 7.33-7.40 (m, 3H), 7.28 (t, J=8.0 Hz, 1H), 6.89˜6.98 (m, 2H),5.42 (s, 2H), 3.61 (t, J=6.4 Hz, 2H), 3.07 (t, J=8 Hz, 2H), 1.83 (q,J=7.6 Hz, 2H), 1.51-1.54 (m, 2H), 1.21-1.45 (m, 15H); MS. m/z 446.2,[M+Na]⁺.

11-(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-1-ol (A11)

YD: 43%. H NMR (400 MHz, d4-MeOD) δ8.48 (d, J=8.8 Hz, 1H), 7.52-7.57 (m,3H), 7.46 (d, J=8.4 Hz, 1H), 7.35˜7.39 (m, 2H), 7.31 (d, J=7.2 Hz, 1H),7.14 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.03 (t,J=7.6 Hz, 2H), 1.81 (quin, J=7.2 Hz, 2H), 1.49 (t, J=6.8 Hz, 2H),1.28-1.41 (m, 15H); MS. m/z 462.2, [M+Na]⁺.

2-(9-hydroxynonyl)quinolin-8-ol (B1)

YD: 85%. ¹H NMR (400 MHz, d4-MeOD) δ7.86 (d, J=8.4 Hz, 1H), 7.22 (t,J=7.6 Hz, 1H), 7.03-7.13 (m, 3H), 3.50 (t, J=6.8 Hz, 2H), 2.75 (t, J=8.0Hz, 2H), 1.58 (quin, J=6.8 Hz, 2H), 1.44 (quin, J=6.8 Hz, 2H), 1.10-1.20(m, 11H); HRMS (ESI): Calcd for [C₁₈H₂₅NO₂—Na]⁺: 310.1778, Found:310.1779.

2-(10-hydroxydecyl)quinolin-8-ol (B2)

YD: 85%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.4 Hz, 1H), 7.35 (t, J=6.8Hz, 1H), 7.26-7.28 (m, 2H), 7.11 (d, J=7.2 Hz, 1H), 3.60 (t, J=6.4 Hz,2H), 2.92 (t, J=7.6 Hz, 2H), 1.79 (quin, J=6.8 Hz, 2H), 1.53 (quin,J=6.8 Hz, 2H), 1.27-1.33 (br, 14H); MS. m/z 302.2, [M+H]⁺.

2-(11-hydroxyundecyl)quinolin-8-ol (B3)

YD: 77%. ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=8.4 Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.27-7.31 (m, 2H), 7.14 (dd, J=1.2, 7.6 Hz, 1H), 3.64 (t, J=6.8Hz, 2H), 2.95 (t, J=7.8 Hz, 2H), 1.83 (quin, J=7.8 Hz, 2H), 1.55 (m,2H), 1.28-1.36 (br, 17H); ¹ MS. m/z 316.2, [M+H]⁺.

2-(12-hydroxydodecyl)quinolin-8-ol (B4)

YD: 76%. ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=8.4 Hz, 1H), 7.36 (t, J=8Hz, 1H), 7.25-7.30 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 3.62 (t, J=6.4 Hz,2H), 2.94 (t, J=7.6 Hz, 2H), 1.81 (quin, J=7.6 Hz, 2H), 1.54 (quin,J=6.8 Hz, 2H), 1.29-1.38 (br, 18H); MS. m/z 330.3, [M+H]⁺.

2-(13-hydroxytridecyl)quinolin-8-ol (B5)

YD: 84%. ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=8.4 Hz, 1H), 7.36 (t, J=7.6Hz, 1H), 7.26-7.30 (m, 2H), 7.13 (d, J=7.6 Hz, 1H), 3.62 (t, J=6.8 Hz,2H), 2.95 (t, J=7.6 Hz, 2H), 1.81 (quin, J=7.2 Hz, 2H), 1.54 (quin,J=6.8 Hz, 2H), 1.25-1.34 (br, 20H); MS. m/z 344.3, [M+H]⁺.

2-(14-hydroxytetradecyl)quinolin-8-ol (B6)

YD: 87%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.8 Hz, 1H), 7.36 (t, J=7.6Hz, 1H), 7.25-7.29 (m, 2H), 7.12 (d, J=7.2 Hz, 1H), 3.61 (t, J=6.4 Hz,2H), 2.94 (t, J=7.6 Hz, 2H), 1.80 (quin, J=7.2 Hz, 2H), 1.54 (quin,J=6.8 Hz, 2H), 1.24-1.34 (br, 24H); MS. m/z 358.3, [M+H]⁺.

2-(15-hydroxypentadecyl)quinolin-8-ol (B7)

YD: 83%. ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=8.4 Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 7.26-7.29 (m, 2H), 7.13 (d, J=7.2 Hz, 1H), 3.62 (t, J=6.8 Hz,2H), 2.95 (t, J=7.6 Hz, 2H), 1.80 (quin, J=7.2 Hz, 2H), 1.54 (quin,J=7.2 Hz, 2H), 1.24-1.37 (br, 24H); MS. m/z 372.3, [M+H]⁺.

2-(11-hydroxyundecyl)-5-methylquinolin-8-ol (B8)

YD: 83%. ¹H NMR (400 MHz, d4-MeOD) δ8.26 (d, J=8.4 Hz, 1H), 7.39 (d,J=8.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.93 (d, J=3.2 Hz, 1H), 3.52 (t,J=6.4 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 2.53 (s, 3H), 1.81 (quin, J=7.2Hz, 2H), 1.48 (quin, J=6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 330.3,[M+H]⁺.

2-(11-hydroxyundecyl)-6-methylquinolin-8-ol (B9)

YD: 83%. ¹H NMR (400 MHz, d4-MeOD) δ7.99 (d, J=8.4 Hz, 1H), 7.29 (d,J=8.8 Hz, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 3.51 (t, J=6.4 Hz, 2H), 2.90(t, J=8.0 Hz, 2H) 2.41 (s, 3H), 1.77 (quin, J=6.4 Hz, 2H), 1.49 (quin,J=6.8 Hz, 2H), 1.25-1.37 (m, 19H); MS. m/z 352.2, [M+Na]⁺.

5-chloro-2-(11-hydroxyundecyl)quinolin-8-ol (B10)

¹H NMR (400 MHz, d4-MeOD) δ8.39 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz,1H), 7.41 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 3.51 (t, J=6.4 Hz,2H), 2.98 (t, J=8.0 Hz, 2H), 1.81 (quin, J=7.2 Hz, 2H), 1.50 (quin,J=6.8 Hz, 2H), 1.27-1.35 (m, 15H); MS. m/z 350.2, [M+H]⁺.

Example 2—Preparation of (8-methoxyquinol-2-yl)alkyl alcohols

Reagents and conditions: (a) MeI, K₂CO₃, acetone, r.t, 10 h.; (b) 1)LHMDS, THF, 0° C., 1 h.; 2) Br(CH₂)_(n−1)OH, rt, 12-30 h.

Method: Methyl iodide (10.8 g, 76.3 mmol) was added to a stirredsolution of 2-methylquinaldine (1.0 g, 6.3 mmol) and K₂CO₃ (5.0 g, 36.2mmol) in 30 ml acetone at RT for 10 h. The reaction mixture was filteredand filtrate removed under a reduced pressure. The residue was purifiedby flash column chromatography with Hex/EA (3:1) and recrystallized withHexane/EA to give 8-methoxy-2-methylauinoline as intermediates. LHMDS(2.2 to 2.5 equiv.) was treated with a stirred solution of intermediate(1 equiv.) in THF at 0° C. for 1 h. Corresponding Br(CH₂)_(n−1)OH (1.0to 1.2 equiv.) was added to a reaction mixture and recover to RT forfurther 12 to 30 h. The solvent was removed under a reduced pressure.The brown oily residue was purified by flash column chromatography withHex/EA or DCM/EA and recrystallized by Hex/EA to afford series ofcompounds C.

9-(8-methoxyquinolin-2-yl)nonan-1-ol (C1)

YD: 50%. ¹H NMR (400 MHz, CDCl₃) δ8.05 (d, J=8.4 Hz, 1H), 7.33-7.42 (m,3H), 7.04 (d, J=6.8 Hz, 1H), 4.08 (s, 3H), 3.62 (t, J=6.4 Hz, 2H), 3.07(t, J=7.6 Hz, 2H), 1.79 (br, 2H), 1.53 (br, 2H), 1.30-1.42 (br, 11H);MS. m/z 324.0, [M+Na]⁺.

10-(8-methoxyquinolin-2-yl)decan-1-ol (C2)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J=8.4 Hz, 1H), 7.36 (t,J=7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.00 (d, J=7.6 Hz, 1H), 4.05 (s, 3H),3.60 (t, J=6.8 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 1.79 (quin, J=8 Hz, 2H),1.52 (quin, J=6.8 Hz, 2H), 1.30-1.43 (br, 12H); MS. m/z 316.2, [M+H]⁺.

11-(8-methoxyquinolin-2yl)undecan-1-ol (C3)

YD: 42%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.8 Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.31-7.34 (m, 2H), 7.15 (d, J=7.2 Hz, 1H), 4.06 (s, 3H), 3.61(t, J=6.8 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 1.79 (quin, J=7.6 Hz, 2H),1.54 (quin, J=6.8 Hz, 2H), 1.31-1.42 (br, 15H); MS. m/z 352.2, [M+Na]⁺.

12-(8-methoxyquinolin-2-yl)dodecan-1ol (C4)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.8 Hz, 1H), 7.35 (t, J=7.6Hz, 1H), 7.30-7.32 (m, 2H), 7.01 (d, J=7.2 Hz, 1H), 4.05 (s, 3H), 3.61(t, J=6.4 Hz, 2H), 3.01 (t, J=8 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H),1.36-1.41 (m, 2H), 1.24-1.33 (br, 16H); MS. m/z 344.3, [M+H]⁺.

13-(8-methoxyquinolin-2-yl)tridecan-1-ol (C5)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.4 Hz, 1H), 7.37 (t, J=7.6Hz, 1H), 7.30-7.33 (m, 2H), 7.01 (d, J=7.6 Hz, 1H), 4.05 (s, 3H), 3.61(t, J=7.2 Hz, 2H), 3.01 (t, J=8 Hz, 2H), 1.80 (quin, J=7.6 Hz, 2H), 1.54(quin, J=6.8 Hz, 2H), 1.36-1.43 (br, 19H); MS. m/z 358.3, [M+H]⁺.

14-(8-methoxyquinolin-2-yl)tetradecan-1ol (C6)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.4 Hz, 1H), 7.31-7.38 (m,3H), 7.01 (d, J=7.2 Hz, 1H), 4.06 (s, 3H), 3.61 (t, J=6.8 Hz, 2H), 3.02(t, J=8 Hz, 2H), 1.79 (quin, J=7.6 Hz, 2H), 1.54 (quin, J=6.8 Hz, 2H),1.23-1.40 (br, 21H); MS. m/z 394.3, [M+Na]⁺.

15-(8-methoxyquinolin-2-yl)pentadecan-1-ol (C7)

YD: 31%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.4 Hz, 1H), 7.31-7.39 (m,3H), 7.01 (d, J=7.2 Hz, 1H), 4.06 (s, 3H), 3.63 (t, J=6.8 Hz, 2H), 3.02(t, J=8 Hz, 2H), 1.79 (quin, J=7.6 Hz, 2H), 1.54 (quin, J=6.8 Hz, 2H),1.32-1.43 (br, 23H); MS. m/z 408.3, [M+H]⁺.

11-(8-methoxy-5-methylquinolin-2-yl)undecan-1-ol(C8)

YD: 30%. ¹H NMR (400 MHz, d4-MeOD) δ8.29 (d, J=8.4 Hz, 1H), 7.43 (d,J=8.8 Hz, 1H), 7.24 (dd, J=8.0, 0.8 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H),4.00 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.56 (s,3H), 1.76 (quin, J=7.6 Hz, 2H), 1.50 (quin, J=7.2 Hz, 2H), 1.27-1.40(br, 15H); MS. m/z 366.2, [M+Na]⁺.

11-(5fluoro-8-methoxyquinolin-2-yl)undecan-1-ol (C9)

¹H NMR (400 MHz, d4-MeOD) δ8.34 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.8 Hz,1H), 7.15 (d, J=7.2 Hz, 1H), 6.93 (d, J=3.2 Hz, 1H), 4.02 (s, 3H), 3.52(t, J=6.8 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 1.81 (quin, J=7.2 Hz, 2H),1.48 (quin, J=6.8 Hz, 2H), 1.13-1.37 (m, 15H); MS. m/z 370.2, [M+Na]⁺.

12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-1ol (C10)

YD: 38%. ¹H NMR (400 MHz, d4-MeOD) δ8.36 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.08 (dd, J=8.4, 4.8 Hz, 1H),4.04 (s, 3H), 3.53 (t, J=6.8 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 1.78(quin, J=7.2 Hz, 2H), 1.51 (quin, J=7.2 Hz, 2H), 1.28-1.42 (m, 17H); MS.m/z 384.2, [M+Na]⁺.

9-(5-chloro-8-methoxyquinolin-2-yl)nonan-1-ol (C11)

YD: 38%. ¹H NMR (400 MHz, d4-MeOD) δ8.47 (d, J=8.8 Hz, 1H), 7.55 (d,J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.04 (s,3H), 3.51 (t, J=6.8 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 1.77 (quin, J=7.6Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.30-1.37 (m, 11H); MS. m/z 336.2,[M+H]⁺.

11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1ol (C12)

YD: 35%. ¹H NMR (400 MHz, d4-MeOD) δ8.46 (d, J=8.4 Hz, 1H), 7.54 (d,J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.04 (s,3H), 3.51 (t, J=6.8 Hz, 2H), 2.99 (t, J=8.0 Hz, 2H), 1.76 (quin, J=7.6Hz, 2H), 1.49 (quin, J=6.8 Hz, 2H), 1.27-1.38 (br, 15H); MS. m/z 386.2,[M+Na]⁺.

15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-1-ol (C13)

YD: 39%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.44 (d, J=8.4 Hz, 1H), 7.47(d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.01 (dd, J=8.4, 4.0 Hz, 1H),4.03 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.99 (t, J=8.0 Hz, 2H), 1.76(quin, J=7.6 Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.22-1.38 (m, 23H); MS.m/z 442.3, [M+Na]⁺.

11-(5-bromo-8-methoxyquinolin-2-yl)undecan-1ol (C14)

YD: 46%. ¹H NMR (400 MHz, CDCl₃) δ8.40 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 4.06 (s, 3H),3.63 (t, J=6.8 Hz, 2H), 3.07 (t, J=8.0 Hz, 2H), 1.79 (quin, J=7.6 Hz,2H), 1.55 (quin, J=6.8 Hz, 2H), 1.30-1.45 (br, 15H); MS. m/z 430.2,[M+Na]⁺.

11-(8methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-ol (C15)

YD: 36%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.40 (dq, J=10.4, 1.6 Hz, 1H),7.86 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H),4.11 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 1.78(quin, J=7.6 Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.27-1.43 (m, 15H); MS.m/z 420.2, [M+Na]⁺.

11-(5,8-dimethoxyquinolin-2-yl)undecan-1-ol (C16)

YD: 31%; ¹H NMR (400 MHz, d4-MeOD) δ8.46 (d, J=8.4 Hz, 1H), 7.38 (d,J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 3.98 (s,3H), 3.94 (s, 3H), 3.51 (t, J=6.8 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 1.73(quin, J=7.6 Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.27-1.35 (br, 15H);MS. m/z 360.2, [M+H]⁺.

11-(8-methoxy-6-methylquinolin-2-yl)undecan-1-ol (C17)

YD: 41%. ¹H NMR (400 MHz, CDCl₃) δ7.96 (d, J=8.4 Hz, 1H), 7.30 (t, J=8.4Hz, 1H), 7.12 (s, 1H), 6.87 (s, 1H), 4.06 (s, 3H), 3.63 (t, J=6.8 Hz,2H), 3.05 (t, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.79 (quin, J=8.0 Hz, 2H),1.55 (quin, J=6.8 Hz, 2H), 1.27-1.41 (br, 15H); MS. m/z 366.2, [M+Na]⁺.

11-(6-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol (C18)

YD: 41%; ¹H NMR (400 MHz, d4-MeOD) δ8.12 (d, J=8.4 Hz, 1H), 7.44 (d,J=8.8 Hz, 1H), 7.07 (dd, J=9.2, 2.4 Hz, 1H), 7.01 (dd, J=10.8, 2.8 Hz,1H), 4.06 (s, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.95 (t, J=8.0 Hz, 2H), 1.75(quin, J=7.6 Hz, 2H), 1.48 (quin, J=7.2 Hz, 2H), 1.19-1.35 (m, 15H); MS.m/z 348.2, [M+H]⁺.

11-(6-chloro-8-methoxyquinolin-2-yl)undecan-1-ol (C19)

YD: 39%; ¹H NMR (400 MHz, d4-MeOD) δ8.11 (d, J=8.4 Hz, 1H), 7.44-7.47(m, 2H), 7.13 (d, J=2.0 Hz, 1H), 4.05 (s, 3H), 3.52 (t, J=6.8 Hz, 2H),2.96 (t, J=8.0 Hz, 2H), 1.76 (quin, J=7.2 Hz, 2H), 1.50 (quin, J=6.8 Hz,2H), 1.28-1.36 (br, 15H); MS. m/z 360.2, [M+H]⁺.

11-(7-fluoro-8-methoxyquinolin-2-yl)undecan-1ol (C20)

YD: 32%; ¹H NMR (400 MHz, d4-MeOD) δ8.20 (d, J=8.8 Hz, 1H), 7.60 (dd,J=8.8, 5.6 Hz, 1H), 7.39 (dd, J=8.8, 1.6 Hz, 1H), 7.01 (d, J=8.8 Hz,1H), 4.13 (d, J=1.2 Hz, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz,2H), 1.80 (quin, J=7.6 Hz, 2H), 1.48 (quin, J=6.8 Hz, 2H), 1.29-1.42 (m,15H); MS. m/z 348.2, [M+H]⁺.

11-(7-chloro-8-methoxyquinolin-2-yl)undecan-1-ol (C21)

YD: 17%; ¹H NMR (400 MHz, d4-MeOD) δ8.20 (d, J=8.4 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 4.08 (s,3H), 3.52 (t, J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 1.82 (quin, J=7.2Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.28-1.42 (br, 15H); MS. m/z 360.2,[M+H]⁺.

11-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-1-ol (C22)

YD: 32%; ¹H NMR (400 MHz, d4-MeOD) δ8.40 (d, J=8.8 Hz, 1H), 7.46 (d,J=8.8 Hz, 1H), 7.07 (s, 1H), 4.08 (s, 3H), 4.02 (s, 3H), 3.51 (t, J=6.8Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 1.74 (quin, J=7.6 Hz, 2H), 1.50 (quin,J=6.8 Hz, 2H), 1.27-1.34 (br, 15H); MS. m/z 394.2, [M+H]⁺.

11-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-1-ol (C23)

YD: 35%; ¹H NMR (400 MHz, d4-MeOD) δ8.38 (d, J=8.8 Hz, 1H), 7.51 (d,J=8.4 Hz, 1H), 7.12 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.52 (t, J=6.4Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 1.74 (quin, J=7.6 Hz, 2H), 1.50 (quin,J=6.8 Hz, 2H), 1.34-1.41 (br, 15H); MS. m/z 394.2, [M+H]⁺.

11-(5,7-dichloro-8-methoxyquinolin-2yl)undecan-1-ol (C24)

YD: 40%. ¹H NMR (400 MHz, CDCl₃) δ8.40 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.56 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.19 (s, 3H), 3.63 (t,J=6.8 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 1.84 (quin, 7.2 Hz, 2H), 1.55(quin, J=6.8 Hz, 2H), 1.27-1.40 (br, 15H); MS. m/z 420.2, [M+Na]⁺.

Example 3—Preparation of (8-ethoxyquinol-2-yl) and(8-Isopropoxyquinol-2-yl)alkyl alcohols

Reagents and conditions: (a) Ethyl iodide or 2-bromopropane, K₂CO₃, DMF,60° C., 14 h.; (b) 1) LHMDS, THF, 0° C., 1 h.; 2) Br(CH₂)_(n−1)OH, RT,12-30 h.

Method: Ethyl iodide (3.9 g, 25.0 mmol) or 2-bromopropane (2.4 g, 19.2mmol) was added to a stirred solution of 2-methylquinaldine (3.0 g, 18.8mmol) and K₂CO₃ (6.5 g 47 mmol; 5.2 g, 37.6 mmol) in 30 ml DMF at 60° C.for 14 h. The reaction mixture was quenched by H₂O (200 ml) andextracted with EtOAc (50 ml×2). The organic layer was concentrated byevaporation in vacuum. The residue was purified by flash columnchromatography with Hex/EA (6:1) and recrystallized with Hexane/EA togive 8-ethoxy-2-methylquinoline as intermediate (2.75 g, 78%) in solidbut liquid form for 8-isoprpopxy-2-methylquinoline (2.92 g, 77%). LHMDS(2.2 equiv.) was treated with a stirred solution of differentintermediates in THF solution at 0° C. for 1 h. CorrespondingBr(CH₂)_(n−1)OH (1.1-1.2 equiv.) was added to a reaction mixture andrecover to RT for further 12 to 30 h. The solvent was removed under areduced pressure. The brown oily residue was purified by flash columnchromatography with Hex/EA or DCM/BA and recrystallized by Hexane/EA toafford compound D and E.

9-(8-ethoxyquinolin-2-yl)nonan-1-ol (D1)

YD: 45%. ¹H NMR (400 MHz, CDCl₃) δ8.07 (d, J=8.0 Hz, 1H), 7.34-7.42 (m,3H), 7.06 (d, J=8.4 Hz, 1H), 4.35 (q, J=6.8 Hz, 2H), 3.63 (t, J=6.8 Hz,2H), 3.11 (br, 2H), 1.83 (quin, J=7.6 Hz, 2H), 1.52-1.64 (m, 5H),1.26-1.46 (br, 11H); MS. m/z 338.0, [M+Na]⁺.

10-(8-ethoxyquinolin-2-yl)decan-1-ol (D2)

YD: 36%. ¹H NMR (400 MHz, d4-MeOD) δ8.16 (d, J=8.4 Hz, 1H), 7.38-7.44(m, 3H), 7.14 (dd, J=7.2, 1.6 Hz, 1H), 4.29 (q, J=6.8 Hz, 2H), 3.52 (t,J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H), 1.57(t, J=7.6 Hz, 3H), 1.50 (t, J=7.6 Hz, 2H), 1.30-1.43 (br, 13H); MS. m/z352.0, [M+Na]⁺.

11-(8-ethoxyquinolin-2-yl)undecan-1-ol (D3)

YD: 43%. ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=7.6 Hz, 1H), 7.31-7.41 (m,3H), 7.04 (d, J=7.2 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.62 (t, J=6.4 Hz,2H), 3.06 (br, 2H), 1.81 (quin, J=8.0 Hz, 2H), 1.51-1.61 (m, 6H),1.38-1.51 (br, 14H); MS. m/z 344.3, [M+H]⁺.

12-(8-ethoxyquinolin-2-yl)dodecan-1-ol (D4)

YD: 33%. ¹H NMR (400 MHz, CDCl₃) δ8.03 (d, J=8.4 Hz, 1H), 7.31-7.39 (m,3H), 7.04 (d, J=7.6 Hz, 1H), 4.33 (q, J=6.8 Hz, 2H), 3.62 (t, J=6.4 Hz,2H), 3.05 (t, J=8.0 Hz, 2H), 1.82 (quin, J=7.2 Hz, 2H), 1.53-1.62 (m,5H), 1.27-1.42 (br, 17H); MS. m/z 380.3, [M+Na]⁺.

13-(8-ethoxyquinolin-2-yl)tridecan-1-ol (D5)

YD: 43%. ¹H NMR (400 MHz, CDCl₃) δ8.04 (d, J=8.4 Hz, 1H), 7.32-7.40 (m,3H), 7.04 (d, J=7.6 Hz, 1H), 4.34 (q, J=6.8 Hz, 2H), 3.62 (t, J=6.4 Hz,2H), 3.07 (t, J=8.0 Hz, 2H), 1.82 (quin, J=7.6 Hz, 2H), 1.52-1.62 (m,5H), 1.19-1.46 (br, 19H); MS. m/z 394.0, [M+Na]⁺.

14-(8-ethoxyquinolin-2-yl)tetradecan-1-ol (D6)

YD: 35%. ¹H NMR (400 MHz, CDCl₃) δ8.00 (d, J=8.4 Hz, 1H), 7.28-7.35 (m,3H), 7.02 (d, J=7.2 Hz, 1H), 4.32 (q, J=6.8 Hz, 2H), 3.61 (t, J=6.4 Hz,2H), 3.01 (t, J=8.0 Hz, 2H), 1.80 (quin, J=7.6 Hz, 2H), 1.52-1.60 (m,5H), 1.24-1.41 (br, 21H); MS. m/z 408.3, [M+Na]⁺.

15-(8-ethoxyquinolin-2-yl)pentadecan-1-ol (D7)

YD: 33%. ¹H NMR (400 MHz, d4-MeOD) δ8.21 (d, J=8.4 Hz, 1H), 7.40-7.47(m, 3H), 7.17 (dd, J=7.2, 1.6 Hz, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.52 (t,J=6.8 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H), 1.57(t, J=6.8 Hz, 3H), 1.51 (quin, J=6.8 Hz, 2H), 1.26-1.43 (br, 23H); MS.m/z 400.4, [M+Na]⁺.

11-(8-ethoxy-5-methylquinolin-2-yl)undecan-1-ol (D8)

YD: 34%. ¹H NMR (400 MHz, CDCl₃) δ8.20 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.31 (q, J=6.8Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 3.08 (t, J=8.0 Hz, 2H), 2.57 (s, 3H),1.83 (quin, J=7.6 Hz, 2H), 1.83 (t, J=7.6 Hz, 3H), 1.57 (quin, J=7.2 Hz,2H), 1.41-1.45 (m, 2H), 1.28-1.33 (br, 13H), MS. m/z 380.2, [M+Na]⁺.

11-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-1-ol (D9)

YD: 49%. ¹H NMR (400 MHz, d4-MeOD) δ8.33 (d, J=8.4 Hz, 1H), 7.49 (d,J=8.8 Hz, 1H), 7.12 (t, J=9.2 Hz, 1H), 7.05 (dd, J=8.4, 4.8 Hz, 1H),4.25 (q, J=7.2 Hz, 2H), 3.51 (t, J=6.8 Hz, 2H), 2.99 (t, J=8.0 Hz, 2H),1.77 (quin, J=7.2 Hz, 2H), 1.55 (t, J=7.2 Hz, 3H), 1.48-1.52 (m, 2H),1.28-1.46 (br, 15H); MS. m/z 384.2, [M+Na]⁺.

9-(5-8-ethoxyquinolin-2-yl)nonan-1-ol (D10)

YD: 34%. ¹H NMR (400 MHz, d4-MeOD) δ8.47 (d, J=8.8 Hz, 1H), 7.55 (d,J=8.8 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 4.28 (q,J=6.8 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 1.76(quin, J=7.6 Hz, 2H), 1.56 (t, J=6.8 Hz, 3H), 1.48-1.51 (m, 2H),1.31-1.46 (br, 11H); MS. m/z 350.2, [M+H]⁺.

11-(5-chloro-8-ethoxyquinolin-2-yl)undecan-1-ol (D11)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ8.35 (d, J=8.8 Hz, 1H), 7.36 (dd,J=8.4, 3.6 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 4.25(q, J=7.2 Hz, 2H), 3.56 (t, J=6.4 Hz, 2H), 2.98 (t, J=8.0 Hz, 2H), 1.76(quin, J=8.0 Hz, 2H), 1.45-1.54 (m, 5H), 1.19-1.39 (br, 15H); MS. m/z400.2, [M+Na]⁺.

15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-1-ol (D12)

YD: 38%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.47 (d, J=8.8 Hz, 1H), 7.53(d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 4.28(q, J=6.8 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 1.79(quin, J=7.6 Hz, 2H), 1.57 (t, J=6.8 Hz, 3H), 1.49 (quin, J=6.8 Hz, 2H),1.25-1.4.1 (br, 23H); MS. m/z 434.3, [M+H]⁺.

11-(5-bromo-8-ethoxyquinolin-2-yl)undecan-1-ol (D13)

YD: 33%. ¹H NMR (400 MHz, d4-MeOD) δ 8.41 (d, J=8.8 Hz, 1H), 7.67 (d,J=8.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 4.2 (q,J=7.2 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 1.77(quin, J=7.6 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H), 1.47-1.57 (m, 2H),1.27-1.39 (br, 15H); MS. m/z 444.2, [M+Na]⁺.

11-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-1-ol (D14)

YD: 34%. ¹H NMR (400 MHz, d4-MeOD) δ8.43 (d, J=8.8 Hz, 1H), 7.64 (s,1H), 7.51 (d, J=8.4 Hz, 1H), 4.39 (q, J=6.8 Hz, 2H), 3.52 (t, J=6.8 Hz,2H), 3.00 (t, J=7.2 Hz, 2H), 1.84 (quin, J=7.2 Hz, 2H), 1.45-1.49 (m,5H), 1.27-1.36 (br, 15H); MS. m/z 434.2, [M+Na]⁺.

9-(8-isopropoxyquinolin-2-yl)nonan-1-ol (E1)

YD: 28%. ¹H NMR (400 MHz, d4-MeOD) δ 8.07 (d, J=8.8 Hz, 1H), 7.33-7.36(m, 1H), 7.31-7.33 (m, 2H), 7.09 (d, J=7.2 Hz, 1H), 4.79 (m, 1H), 3.49(t, J=6.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 1.71 (quin, J=7.6 Hz, 2H),1.45-1.49 (m, 2H), 1.41 (d, J=6 Hz, 6H), 1.20-1.35 (br, 11H); MS. m/z330.2, [M+H]⁺.

10-(8-isopropoxyquinolin-2-yl)decan-1-ol (E2)

YD: 36%. ¹H NMR (400 MHz, d4-MeOD) δ 8.14 (d, J=8.8 Hz, 1H), 7.40-7.43(m, 1H), 7.37-7.39 (m, 2H), 7.16 (dd, J=6.8, 2.0 Hz, 1H), 4.83 (m, 1H),3.51 (t, J=6.8 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H), 1.77 (quin, J=7.2 Hz,2H), 1.45-1.49 (m, 2H), 1.41 (d, J=6 Hz, 6H), 1.20-1.35 (br, 11H); MS.m/z 366.0, [M+Na]⁺.

11-(8-isopropoxyquinolin-2-yl)undecan-1-ol (E3)

YD: 45%. ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=8.4 Hz, 1H), 7.34 (d, J=4.4Hz, 2H), 7.24-7.27 (m, 1H), 7.09 (t, J=4.4 Hz, 1H), 4.82 (sept, J=6 Hz,1H), 3.60 (t, J=6.8 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 1.81 (quin, J=7.6Hz, 2H), 1.51-1.56 (m, 2H), 1.47 (d, J=6 Hz, 6H), 1.33-1.43 (br, 15H);MS. m/z 380.3, [M+Na]⁺.

12-(8-isopropoxyquinolin-2-yl)dodecan-1-ol (E4)

YD: 34%. ¹H NMR (400 MHz, CDCl₃) δ8.05 (d, J=7.6 Hz, 1H), 7.30-7.39 (m,3H), 7.13 (dd, J=6.4, 2.4 Hz, 1H), 4.85 (sept, J=6 Hz, 1H), 3.63 (t,J=6.8 Hz, 2H), 3.09 (br, 2H), 1.84 (quin, J=7.6 Hz, 2H), 1.56 (quin,J=7.2 Hz, 2H), 1.48 (d, J=6 Hz, 6H), 1.27-1.47 (br, 17H); MS. m/z 394.3,[M+Na]⁺.

13-(8-isopropoxyquinolin-2-yl)tridecan-1-ol (E5)

YD: 34%. ¹H NMR (400 MHz, d4-MeOD) δ8.11 (d, J=8.4 Hz, 1H), 7.35-7.41(m, 3H), 7.14 (d, J=7.2 Hz, 1H), 4.81 (br, 1H), 3.52 (t, J=6.8 Hz, 2H),2.96 (t, J=8.0 Hz, 2H), 1.75 (quin, J=7.2 Hz, 2H), 1.45-1.52 (m, 2H),1.43 (d, J=6.0 Hz, 6H), 1.25-1.42 (br, 19H); MS. m/z 408.0, [M+Na]⁺.

14-(8-isopropoxyquinolin-2-yl)tetradecan-1-ol (E6)

YD: 36%. ¹H NMR (400 MHz, d4-MeOD) δ8.13 (d, J=8.8 Hz, 1H), 7.37-7.43(m, 3H), 7.16 (dd, J=7.2, 1.6 Hz, 1H), 4.86 (br, 1H), 3.52 (t, J=6.8 Hz,2H), 2.98 (t, J=7.6 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H), 1.49-1.52 (m,1H), 1.46 (d, J=6.4 Hz, 6H), 1.26-1.41 (br, 21H); MS. m/z 422.3,[M+Na]⁺.

15-(8-isopropoxyquinolin-2-yl)pentadecan-1-ol (E7)

YD: 36%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.4 Hz, 1H), 7.27-7.36 (m,3H), 7.10-7.13 (m, 1H), 4.82 (sept, J=4.1 Hz, 1H), 3.61 (t, J=6.8 Hz,2H), 3.00 (t, J=6.4 Hz, 2H), 1.81 (quin, J=7.6 Hz, 2H), 1.52-1.55 (m,2H), 1.48 (d, J=2 Hz, 6H), 1.31-1.47 (br, 21H); MS. m/z 436.3, [M+Na]⁺.

11-(8-isopropoxy-5-methylquinolin-2-yl)undecan-1-ol (E8)

YD: 48%. ¹NMR (400 MHz, CDCl₃) δ8.09 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.8Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 4.75 (sept, J=6Hz, 1H), 3.55 (t, J=6.8 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 2.51 (s, 3H),1.81 (t, J=7.2 Hz, 2H), 1.23-1.49 (br, 23H); MS. m/z 394.3, [M+Na]⁺.

11(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-1-ol (E9)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ8.30 (d, J=8.8 Hz, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.09 (d, J=4.8 Hz, 1H), 4.79 (m, 1H), 3.51 (t, J=6.8 Hz,2H), 2.97 (t, J=8.0 Hz, 2H), 1.74 (quin, J=7.6 Hz, 2H), 1.45-1.51 (m,2H), 1.42 (d, J=6.4 Hz, 6H), 1.12-1.39 (br, 15H); MS. m/z 398.2,[M+Na]⁺.

9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-1-ol (E10)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ8.45 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.4 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.85 (m,1H), 3.51 (t, J=6.4 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 1.78 (quin, J=7.6Hz, 2H), 1.49 (quin, J=6.4 Hz, 2H), 1.45 (d, J=6.0 Hz, 6H), 1.30-1.42(br, 11H); MS. m/z 364.2, [M+Na]⁺.

11-(5-chloro-8-isopropoxyquinolin-2-yl)undecan-1-ol (E11)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ8.47 (d, J=8.4 Hz, 1H), 7.53 (d,J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.89 (m,1H), 3.52 (t, J=6.4 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 1.79 (quin, J=7.6Hz, 2H), 1.48 (quin, J=6.8 Hz, 2H), 1.41 (d, J=5.6 Hz, 6H), 1.21˜1.39(br, 15H); MS. m/z 414.2, [M+Na]⁺.

15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1-ol (E12)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.46 (d, J=8.8 Hz, 1H), 7.51(d, J=8.8 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.85(m, 1H), 3.52 (t, J=6.8 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 1.79 (quin,J=7.2 Hz, 2H), 1.51 (quin, J=6.8 Hz, 2H), 1.46 (d, J=6.0 Hz, 6H),1.25-1.39 (m, 23H); MS. m/z 448.3, [M+Na]⁺.

11-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-1-ol (E13)

YD: 40%. ¹H NMR (400 MHz, d4-MeOD) δ8.43 (d, J=8.8 Hz, 1H), 7.69 (d,J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 4.86 (br,1H) 3.52 (t, J=6.8 Hz, 2H) 3.02 (t, J=7.6 Hz, 2H), 1.79 (quin, J=7.2 Hz,2H), 1.50-1.52 (m, 2H), 1.46 (d, J=6.0 Hz, 6H), 1.28-1.41 (br, 15H); MS.m/z 458.2, [M+Na]⁺.

11-(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-1-ol (E14)

YD: 37%. ¹H NMR (400 MHz, CDCl₃) δ8.36 (d, J=8.4 Hz, 1H), 7.56 (d, J=3.2Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 5.13 (m, 1H), 3.63 (t, J=6.8 Hz, 2H),3.00 (t, J=7.6 Hz, 2H), 1.86 (quin, J=6.8 Hz, 2H), 1.52-1.59 (m, 4H),1.27-1.44 (br, 20H); MS. m/z 448.4, [M+Na]⁺.

Example 4—Preparation of (8-cyclopropylmethylenoxyquinol-2-yl)alkylalcohol derivatives

Reagents and conditions: (a) Methylenecyclopropoyl bromide, K₂CO₃, DMF,60° C., 13 h.; (b) 1) LHMDS, THF, 0° C., 1 h.; 2) Br(CH₂)_(n−1)OH, rt,12-20 h.

Method: Methylenecyclopropyl bromide (1.0 g, 6.3 mmol) was added to astirred solution of 2-methylquinoline (1.0 g, 6.3 mmol) and K₂CO₃ (2.5g, 18.1 mmol) in 25 ml DMF at 60° C. for 13 h. The reaction mixture wasquenched by H₂O (200 ml) and extracted with EtOAc (30 ml×3). The organiclayer was concentrated by evaporation in vacuum and the residue purifiedby flash column chromatography with Hex/EA (8:1 to 6:1) to give5-chloro-8-(cyclopropylmethoxy)-2-methylquinoline as intermediate. LHMDS(2.2 equiv.) was treated with a stirred solution of intermediate (0.5 g,2.3 mmol) in THF solution at 0° C. for 1 h. CorrespondingBr(CH₂)_(n−1)OH (1.1-1.2 equiv.) was added to reaction mixture andrecover to RT for further 12 to 20 h. The solvent was removed under areduced pressure. The brown oily residue was purified by flash columnchromatography with Hex/EA or DCM/EA and recrystallized by Hex/EA toafford compound F.

9-(8-cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol (F1)

YD: 49%. ¹H NMR (400 MHz, d4-MeOD) δ8.15 (d, J=8.4 Hz, 1H), 7.38-7.43(m, 3H), 7.14 (dd, J=5.6, 3.2 Hz, 1H), 4.06 (d, J=7.2 Hz, 2H), 3.51 (t,J=6.8 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 1.77 (quin, J=7.6 Hz, 2H),1.48-1.52 (m, 3H), 1.32-1.47 (m, 1H), 0.65-0.70 (m, 2H), 0.34-0.45 (m,2H); MS. m/z 342.2, [M+H]⁺.

10-(8-cyclopropylmethoxy)quinolin-2-yl)decan-1-ol (F2)

YD: 43%. ¹H NMR (400 MHz, d4-MeOD) δ8.16 (d, J=8.4 Hz, 1H), 7.40-7.43(m, 3H), 7.15 (dd, J=5.6, 3.2 Hz, 1H), 4.07 (d, J=7.2 Hz, 2H), 3.52 (t,J=6.4 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 1.80 (quin, J=7.6 Hz, 2H),1.47-1.53 (m, 3H), 1.31-1.44 (m, 13H), 0.67-0.69 (m, 2H), 0.44-0.46 (m,2H); MS. m/z 356.2, [M+H]⁺.

11-(8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol (F3)

YD: 45%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.4 Hz, 1H), 7.30-7.38 (m,2H), 7.05 (dd, J=6.4, 2.4 Hz, 1H), 4.11 (d, J=6.8 Hz, 1H), 3.63 (t,J=6.4 Hz, 2H), 3.04 (t, J=8.0 Hz, 2H), 1.83 (quin, J=7.6 Hz, 2H),1.48-1.59 (m, 3H), 1.26-1.46 (br, 15H), 0.67 (dd, J=13.2, 5.6 Hz, 2H),0.44 (dd, J=13.2, 5.6 Hz, 2H); MS. m/z 392.2, [M+Na]⁺.

12-(8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-1-ol (F4)

YD: 36%. ¹H NMR (400 MHz, CDCl₃) δ8.01 (d, J=8.4 Hz, 1H), 7.29-7.38 (m,3H), 7.06 (dd, J=6.0. 2.4 Hz, 1H), 4.11 (d, J=6.8 Hz, 1H), 3.63 (t,J=6.4 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H), 1.83 (quin, J=7.6 Hz, 2H),1.48-1.59 (m, 3H), 1.27-1.47 (br, 17H), 0.67 (dd, J=13.2, 5.6 Hz, 2H),0.42-0.48 (m, 2H); MS. m/z 384.3, [M+H]⁺.

13-(8-(cyclopropylmethoxy)quinolin-2-yl)tridecan-1-ol (F5)

YD: 42%. ¹H NMR (400 MHz, d4-MeOD) δ8.14 (d, J=8.4 Hz, 1H), 7.38˜7.41(m, 3H), 7.05 (dd, J=5.6, 3.2 Hz, 1H), 4.05 (d, J=6.8 Hz, 2H), 3.52 (t,J=6.4 Hz, 2H), 2.99 (t, J=8.0 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H),1.44-1.52 (m, 3H), 1.26-1.40 (m, 19H), 0.67 (dd, J=13.2, 5.6 Hz, 2H),0.40-0.47 (m, 2H); MS. m/z 420.0, [M+Na]⁺.

14-(8-(cyclopropylmethoxy)quinolin-2-yl)tetradecan-1-ol (F6)

YD: 37%. ¹H NMR (400 MHz, d4-MeOD) δ8.15 (d, J=8.8 Hz, 1H), 7.39-7.42(m, 3H), 7.13 (dd, J=5.6, 3.2 Hz, 1H), 4.05 (d, J=6.8 Hz, 2H), 3.52 (t,J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 1.78 (quin, J=7.6 Hz, 2H),1.44-1.52 (m, 3H), 1.26-1.43 (m, 21H), 0.65-0.69 (m, 2H), 0.42 (dd,J=10.0, 4.8 Hz, 2H); MS. m/z 434.3, [M+Na]⁺.

15-(8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol (F7)

YD: 69%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.13 (dd, J=8.4, 2.0 Hz, 1H),7.38 (br, 3H), 7.11 (d, J=2.4 Hz, 1H), 4.05 (d, J=6.8 Hz, 2H), 3.52 (t,J=6.8 Hz, 2H), 2.99 (t, J=8.0 Hz, 2H), 1.78 (quin, J=7.2 Hz, 2H),1.46-1.52 (m, 3H), 1.25-1.44 (m, 23H), 0.63-0.69 (m, 2H), 0.40-0.46 (m,2H); MS. m/z 426.4, [M+H]⁺.

11-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-1-ol (F8)

YD: 45%. ¹H NMR (400 MHz, d4-MeOD) δ8.31 (d, J=8.8 Hz, 1H), δ 7.44 (d,J=8.8 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 4.02 (d,J=7.2 Hz, 2H), 3.52 (t, J=6.4 Hz, 2H), 3.00 (t, J=8.0 Hz, 2H), 2.57 (s,3H), 1.79 (quin, J=7.2 Hz, 2H), 1.29-1.52 (m, 18H), 0.65-0.68 (m, 2H),0.40-0.43 (m, 2H); MS. m/z 406.3, [M+Na]⁺.

11-(8-(cyclopropylmethoxy)-5-fluoroquinolin-2-yl)undecan-1-ol (F9)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ8.36 (d, J=8.8 Hz, 1H), 7.52 (d,J=8.8 Hz, 1H), 7.07-7.15 (m, 2H), 4.05 (d, J=6.8 Hz, 2H), 3.53 (t, J=6.8Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.79 (quin, J=7.6 Hz, 2H), 1.42-1.49(m, 3H), 1.22-1.40 (m, 15H), 0.65-0.69 (m, 2H), 0.42 (dd, J=10.4, 4.8Hz, 2H); MS. m/z 410.2, [M+Na]⁺.

9-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol (F10)

YD: 33%. ¹H NMR (400 MHz, d4-MeOD) δ8.48 (d, J=8.8 Hz, 1H), 7.55 (d,J=8.8 Hz 1H), 7.49 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 4.06 (d,J=6.8 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.03 (t, J=8.0 Hz, 2H), 1.83 (t,J=7.6 Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m,2H), 0.43-0.46 (m, 2H); MS. m/z 376.2, [M+H]⁺.

11-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol (F11)

YD: 34%. ¹H NMR (400 MHz, CDCl₃) δ8.41 (d, J=8.8 Hz, 1H), 7.43 (d, J=2.4Hz 1H), 7.41 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.09 (d, J=7.2Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 3.05 (t, J=8.0 Hz, 2H), 1.83 (t, J=7.6Hz, 2H), 1.54-1.69 (m, 3H), 1.27-1.48 (br, 15H), 0.67-0.71 (m, 2H),0.43-0.46 (m, 2H); MS. m/z 426.2, [M+Na]⁺.

15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol (F12)

YD: 28%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.47 (d, J=8.8 Hz, 1H), 7.54(d, J=8.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 4.06(d, J=6.8 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.79(quin, J=7.6 Hz, 2H), 1.46-1.52 (m, 2H), 1.25-1.44 (br, 24H), 0.65-0.69(m, 2H), 0.41-0.43 (m, 2H); MS. m/z 460.3, [M+Na]⁺.

11-(5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol (F13)

YD: 35%. ¹H NMR (400 MHz, d4-MeOD) δ8.42 (d, J=8.8 Hz, 1H), δ 7.67(J=8.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.05 (d,J=7.2 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.02 (t, J=8.0 Hz, 2H), 1.77(quin, 7.6 Hz, 2H), 1.46-1.52 (m, 3H), 1.28-1.44 (m, 15H), 0.65-0.70 (m,2H), 0.42-0.45 (m, 2H); MS. m/z 470.2, [M+Na]⁺.

11-(5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol (F14)

YD: 53%. ¹H NMR (400 MHz, d4-MeOD) δ8.47 (d, J=8.8 Hz, 1H), δ 7.67 (s,1H), 7.53 (d, J=8.8 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.23 (d, J=7.2 Hz,2H), 3.53 (t, J=6.4 Hz, 2H), 3.02 (t, J=7.6 Hz, 2H), 1.86 (quin, J=7.2Hz, 2H), 1.48-1.53 (m, 2H), 1.29-1.38 (m, 16H), 0.62 (dd, J=12.8, 5.2Hz, 2H), 0.31 (dd, J=10.8, 5.2 Hz, 2H); MS. m/z 460.2, [M+Na]⁺.

Example 5—Preparation of (5,7-dichloro-8-hydroxyquinol-2-yl)alkylalcohol

Reagents and conditions: (a) NCS, CHCl₃, rt, 48 h.

Method: N-chlorosuccinimide (0.3 g, 2.25 mmol) was added to a stirredsolution of compounds B in CHCl₃ (20 ml) for 48 h. The reaction mixturewas poured into crushed ice and extracted with CH₂Cl₂ (20 ml×2). Theextract was purified by column chromatography with Hex/EA (3:1) andrecrystallized to give compound (0.18 g, 49%).

5,7-dichloro-2-(11-hydroxyundecyl)quinolin-8-(G1)

YD: 49%. ¹H NMR (400 MHz, CDCl₃) δ8.38 (d, J=8.8 Hz, 1H), 7.51 (s, 1H),7.42 (d, J=8.8 Hz, 1H), 3.63 (t, J=6.8 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H),1.82 (quin, J=7.2 Hz, 2H), 1.56 (quin, J=7.6 Hz , 2H), 1.27-1.38 (br,15H); MS. m/z 382.0, [M+H]⁺.

Example 6—Preparation of (5-chloro-8-methoxyquinol-2-yl)alkyl alcohol oralkylacetate

Reagents and conditions: (a) HCl, ICl₃, glacial HOAc, H₂O, 6 h, rt.

Method: To a various long chain substituted (8-methoxyquinolin-2-yl)-ol(1.0 eq.) was added conc. HCl (0.5 mL/mmol) at RT and the reddish yellowmixture was stirred for 5 minutes. To this mixture was added dropwise asolution of ICl₃ (1.5 eq.) in conc. HCl (2 mL). The yellow gummy mixturewas stirred at RT for 6 h. Water was added to it and partitioned withEA. Organic layer was washed with brine, drying on anhydrous MgSO₄ andfiltered followed by solvent removal, yielded oily residue purified byflash column chromatography using CHCl₃ to yield H1 to H5.

10-(5-Chloro-8-methoxyquinolin-2-yl)decan-1-ol (H1a) and acetic acid10-(5-chloro-8-methoxyquinolin-2-yl)decyl ester (H1b)

YD: 61% and 10%. H1a: ¹H NMR (200 MHz, CDCl₃) δ8.41 (d, J=8.68 Hz, 1H),7.42 (dd, J=8 Hz, J=2 Hz, 2H), 6.91 (d, J=8 Hz, 1H), 4.03 (s, 3H), 3.59(t, J=6 Hz, 2H), 3.59 (t, J=4 Hz, 2H), 1.73 (m, 2H), 1.48 (m, 2H), 1.25(br, 12H); HRMS (EI): Calcd for C₂₀H₂₈ClNO₂:349.1803, Found: 349.1781.H1b: ¹H NMR (400 MHz, CDCl₃) δ8.41 (d, J=8 Hz, 1H), 7.42 (dd, J=8 Hz,J=4 Hz, 2H), 6.92 (d, J=8 Hz, 1H), 4.06 (t, J=8 Hz, 2H), 4.02 (s, 3H),3.03 (t, J=8 Hz, 2H), 2.02 (s, 3H), 1.79 (m, 2H), 1.59 (m, 2H), 1.40 (m,2H), 1.23 (br, 12H); HRMS (FAB, M+H): Calcd for C₂₂H₃₁ClNO₃ 392.1992,Found 392.1983.

11-(5-Chloro-8-methoxyquinolin-2-yl)undecan-1ol (H2a) and acetic acid11-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester (H2b)

YD: 60% and 12%. H2a: ¹H NMR (400 MHz, CDCl₃) δ8.43 (d, J=8.72 Hz, 1H),7.44 (dd, J=13.5 Hz, J=5.3 Hz, 2H), 6.94 (d, J=8.3 Hz, 1H), 4.05 (s,3H), 3.62 (t, J=6.6 Hz, 2H), 3.07 (t, J=5.2 Hz, 2H), 1.80 (m, 2H), 1.54(m, 2H), 1.39 (m, 2H), 1.26 (br, 12H); HRMS (El): Calcd forC₂₁H₃₀ClNO₂363.1960, Found 363.1941. H2b: ¹H NMR (400 MHz, CDCl₃) δ8.41(d, J=8.6 Hz, 1H), 7.42 (dd, J=8.3 Hz, J=3.8 Hz, 2H), 6.91 (d, J=8.4 Hz,1H), 4.06 (t, J=7.8 Hz, 2H), 4.02 (s, 3H), 3.02 (t, J=7.8 Hz, 2H), 2.01(s, 3H), 1.78 (m, 2H), 1.58 (m, 2H), 1.39 (m, 2H), 1.22 (br, 12H); HRMS(El): Calcd for C₂₃H₃₂ClNO₃ 405.2065, Found 405.2044.

12-(5-Chloro-8-methoxyquinolin-2-yl)dodecan-1-ol (H3a) and acetic acid12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester (H3b)

YD: 57% and 27%. H3a: ¹H NMR (400 MHz, CDCl₃) δ8.46 (d, J=8.6 Hz, 1H),7.44 (dd, J=8.3 Hz, J=6.9 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 4.04 (s, 3H),3.59 (t, J=6.6 Hz, 2H), 3.11 (t, J=7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m,2H), 1.40 (m, 2H), 1.23 (br, 14H); HRMS (El): Calcd for C₂₂H₃₂ClNO₂377.2116, Found 377.2106. H3b: ¹H NMR (200 MHz, CDCl₃) δ8.38 (d, J=8.7Hz, 1H), 7.40 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 4.03 (t, J=7.8Hz, 214), 4.01 (s, 3H), 3.02 (t, J=7.8 Hz, 2H), 1.99 (s, 3H), 1.76 (m,2H), 1.59 (m, 2H), 1.20 (br, 16H); HRMS (FAB, M+H): Calcd forC₂₄H₃₅ClNO₃ 420.2305, Found 420.2310.

13-(5-Chloro-8-methoxyquinolin-2-yl)tridecan-1-ol (H4a) and acetic acid13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester (H4b)

YD: 64% and 14%. H4a: ¹H NMR (400 MHz, CDCl₃) δ8.46 (d, J=8.6 Hz, 1H),7.45 (dd, J=8.3 Hz, J=6.9 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 4.04 (s, 3H),3.59 (t, J=6.6 Hz, 2H), 3.11 (t, J=7.8 Hz, 2H), 1.78 (m, 2H), 1.50 (m,2H), 1.40 (m, 2H), 1.23 (br, 16H); HRMS (El): Calcd for C₂₃H₃₄ClNO₂391.2273, Found 391.2249, H4b: ¹H NMR (400 MHz, CDCl₃) δ 8.38 (d, J=8.6Hz, 1H), 7.40 (dd, J=8.5 Hz, J=5.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 1H), 4.01(t, J=9.6 Hz, 2H), 4.00 (s, 3H), 3.00 (t, J=7.9 Hz, 2H), 1.99 (s, 3H),1.75 (m, 2H), 1.58 (m, 2H), 1.38 (m, 2H), 1.22 (br, 16H); HRMS (FAB,M+H): Calcd for C₂₅H₃₇ClNO₃ 434.2462, Found 434.2459.

Example 7—Preparation of (8-hydroxyquinol-4-yl) or (8-alkoxyquinol-4-yl)alkyl alcohols

Reagents and conditions: (a) methyl vinyl ketone, HCl, reflux, (b) MeI,K₂CO₃, acetone, rt, 8 h; EtI or 2-bromopropane or methylenecyclopropylbromide, K₂CO₃, DMF, 60° C., (c) 1) LHMDS, THF, 0° C., 1 h.; 2)Br(CH₂)_(n−1)OH, rt, (d) BnBr, KOH, EtOH, reflux, (e) H₂, Pd/C, MeOH,rt, 24 h.

Method: The intermediate INT 1 was synthesized through ring closure from2-aminophenol reacted with methyl vinyl ketone. INT 1 was reacted withvarious alkyl halides to afford 8-alkoxy-4methylquinoline derivatives asintermediates. Corresponding Br(CH₂)_(n−1)OH was reacted withintermediates to synthesize series of compounds J and I. The protectivegroup J was removed by hydrogenation (method illustrated in example 1)to obtain compound K.

11-(8-methoxyquinolin-4-yl)undecan-1-ol (I1)

YD: 34%. ¹H NMR (400 MHz, CDCl₃) δ8.80 (dd, J=4.4, 0.6 Hz, 1H), 7.59(dd, J=8.4, 0.8 Hz, 1H), 7.44-7.49 (m, 1H), 7.03 (d, J=7.6 Hz, 1H), 4.08(s, 3H), 3.63 (t, J=6.8 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 1.74 (quin,J=7.6 Hz, 2H), 1.55 (quin, J=7.2 Hz, 2H), 1.23-1.45 (br, 15H), MS. m/z329.9, [M+H]⁺.

11-(8-ethoxyquinolin-4-yl)undecan-1-ol (I2)

YD: 42%. H NMR (400 MHz, d4-MeOD) δ8.66 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.4 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.15 (d,J=7.6 Hz, 1H), 4.27 (q, J=6.8 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 3.08 (d,J=7.6 Hz, 2H), 1.75 (quin, J=7.6 Hz, 2H), 1.50-1.57 (m, 5H), 1.21-1.49(br, 15H); MS. m/z 366.2, [M+Na]⁺.

11-(8-isopropoxyquinolin-4-yl)undecan-1-ol (I3)

YD: 48%. ¹H NMR (400 MHz, d4-MeOD) δ 8.65 (d, J=8.4 Hz, 1H), 7.63 (d,J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 7.17 (d,J=8.0 Hz, 1H), 4.84 (br, 1H), 3.52 (t, J=6.4 Hz, 2H), 3.07 (d, J=7.6 Hz,2H), 1.74 (br, 2H), 1.43-1.50 (br, 9H), 1.29-1.34 (br, 14H); MS. m/z380.3, [M+Na]⁺.

11-(8-cyclopropylmethoxy)quinolin-4-yl)undecan-1-ol (I4)

YD: 53%. ¹H NMR (400 MHz, d4-MeOD) δ8.66 (d, J=8.4 Hz, 1H), 7.63 (d,J=8.4 Hz, 1H), 7.49 (t, J=8.4 Hz, 1H), 7.36 (d, J=4.8 Hz, 1H), 7.13 (d,J=7.6 Hz, 1H), 4.03 (d, J=6.8 Hz, 1H), 3.52 (t, J=6.8 Hz, 2H), 3.06 (d,J=7.6 Hz, 2H), 1.69-1.75 (m, 2H), 1.28-1.52 (br, 18H), 0.65-0.68 (m,2H), 0.42-0.43 (m, 2H); MS. m/z 392.2 [M+Na]⁺.

11-(8-(benzyloxy)quinolin-4-yl)undecan-1-ol (J1)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ 8.66 (d, J=8.4 Hz, 1H), 7.64 (d,J=8.4 Hz, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.30-7.38(m, 3H), 7.26-7.28 (m, 1H), 7.17 (d, J=7.6 Hz, 1H), 5.37 (s, 2H), 3.52(t, J=6.4 Hz, 2H), 3.06 (t, J=8 Hz, 2H), 1.73 (q, J=7.6 Hz, 2H), 1.50(t, J=7.2 Hz, 2H), 1.28-1.48 (m, 15H); MS. m/z 428.3, [M+Na]⁺.

12-(8-(benzyloxy)quinolin-4-yl)dodecan-1-ol (J2)

YD: 46%. ¹H NMR (400 MHz, d4-MeOD) δ 8.67 (d, J=4.4 Hz, 1H), 7.65 (d,J=8.4 Hz, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.30-7.39(m, 3H), 7.27-7.30 (m, 1H), 7.18 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 3.52(t, J=6.4 Hz, 2H), 3.08 (t, J=7.6 Hz, 2H), 1.74 (q, J=7.6 Hz, 2H), 1.49(t, J=7.2 Hz, 2H), 1.23-1.45 (m, 17H); MS. m/z 442.3, [M+Na]⁺.

4-(11-hydroxyundecyl)quinolin-8-ol (K1)

YD: 84%. ¹H NMR (400 MHz, d4-MeOD) δ 8.63 (d, J=4.4 Hz, 1H), 7.51 (d,J=8.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=4.0 Hz, 1H), 7.06 (d,J=7.6 Hz, 1H), 3.51 (t, J=6.8 Hz, 2H), 3.02 (t, J=8.0 Hz, 2H), 1.71 (t,J=7.6 Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.12-1.31 (br, 15H); MS. m/z316.2, [M+H]⁺.

4-(12-hydroxydodecyl)quinolin-8-ol (K2)

YD: 86%. ¹H NMR (400 MHz, CDCl₃) δ8.52 (d, J=4.4 Hz, 1H), 7.36 (dd,J=8.4, 0.8 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.13 (d, J=4.4 Hz, 1H), 6.99(dd, J=7.6, 1.2 Hz, 1H), 3.43 (t, J=6.8 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H),1.61 (quin, J=7.6 Hz, 2H), 1.40 (quin, J=6.8 Hz, 2H), 1.12-1.31 (br,17H); MS. m/z 352.2, [M+Na]⁺.

Example 8 Preparation of (8-trifluoromethoxyquinol-2-yl)alkyl alcohols

Method: The intermediate was synthesized through ring closure from2-trifluoromethoxyaniline reacted with crotonaldehyde. Intermediate wasreacted with corresponding Br(CH₂)_(n−1)OH (as illustrated above) tosynthesize series compounds L.

9-(8-trifluoromethoxy)quinolin-2-yl)nona-1-ol (L1)

YD: 41%. ¹H NMR (400 MHz, CDCl₃) δ8.06 (dd, J=8.4, 1.2 Hz, 1H), 7.70 (d,J=8.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.34 (dd,J=8.4, 1.2 Hz, 1H), 3.61 (t, J=6.4 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H),1.81-1.85 (br, 2H), 1.53-1.56 (br, 2H), 1.21-1.35 (m, 15H); MS. m/z355.9, [M+Na]⁺.

11-(8-trifluoromethoxy)quinolin-2-yl)undecan-1-ol (L2)

YD: 41%. ¹H NMR (400 MHz, d4-MeOD) δ8.26 (t, J=8.0 Hz, 1H), 7.86 (d,J=7.6 Hz, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.47-7.56 (m, 2H), 3.51 (t, J=6.8Hz, 2H) 2.99 (t, J=6.4 Hz, 2H), 1.79 (quin, J=6.8 Hz, 2H), 1.50 (quin,J=6.8 Hz, 2H), 1.21-1.35 (m, 15H); MS. m/z 406.2, [M+Na]⁺.

14-(8-(trifluoromethoxy)quinolin-2-yl)tetradecan-1-ol (L3)

YD: 37%. ¹H NMR (400 MHz, d4-MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.87 (d,J=8.0 Hz, 1H), 7.65 (t, J=7.2 Hz, 1H), 7.49-7.56 (m, 2H), 3.52 (t, J=6.8Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 1.82 (quin, J=7.2 Hz, 2H), 1.51 (quin,J=6.8 Hz, 2H), 1.27-1.37 (m, 21H); MS. m/z 448.2, [M+Na]⁺.

15-(8-(trifluoromethoxy)quinolin-2-yl)pentadecan-1-ol (L4)

YD: 32%. ¹H NMR (400 MHz, d4-MeOD+CDCl₃) δ8.21 (d, J=8.4 Hz, 1H), 7.81(d, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.46(t, J=8.4 Hz, 1H), 3.52 (t, J=6.8 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 1.80(quin, J=7.6 Hz, 2H), 1.50 (quin, J=7.2 Hz, 2H), 1.15-1.41 (br, 23H);MS. m/z 462.2, [M+Na]⁺.

Example 9—Preparation of 2-N-substituted alcohol-8-hydroxyquinoline

Reagents and conditions: (a) SeO₂, dioxane, 50 to 80° C.; (b)N-methylpropagylamine or 2-(piperazin-1-yl) ethanol or NH₂(CH₂)n−1OH,NaBH(OAc)₃, 1,2-dichloroethane, rt.

Method: A solution of 8-hydroxy-2-methylquinoline (6.0 g, 37.7 mmol) indioxane (15 ml) was added to a stirred solution of SeO₂ (6.3 g, 56.8mmol) in dioxane (80 ml) dropwise at 50° C. and the mixture was heatedup to 80° C. for further 20 h. The resulting mixture was filtered. Thefiltrate was concentrated and the residue purified by columnchromatography with Hex/EA=(15:1 to 10:1) to give8-hydroxyquinoline-2-carboxaldehyde (2.45 g, 38%) derivatives asintermediates. Intermediate was converted into N-substituted compoundsby reductive amination with aminoalcohol, aminoalkyne or otherheterocycles to give series of compounds. 8-alkoxy-2-methyl quinolinewere oxidized to give 8-alkoxyquinoline-2-carboxaldehyde derivatives andfollowed by the same method to give compounds M to O.

2-((4-2-hydroxyethyl)piperazin-1-yl)methyl)quinolin-8-ol (M1)

YD: 76%. ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.10 (d, J=6.8Hz, 1H), 3.73 (s, 2H), 3.61 (t, J=6.8 Hz, 2H), 2.51 (t, J=5.6 Hz, 10H);HRMS (ESI): Calcd for [M+Na]⁺: 310.1526, Found: 310.1527.

2-(4-((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol(M2)

YD: 76%. ¹H NMR (400 MHz, CDCl₃) δ8.23 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 3.81 (s, 3H),3.72 (s, 2H), 3.44 (t, J=4.8 Hz, 2H), 2.35-2.38 (m, 10H); MS. m/z 336.1,[M+H]⁺.

2-(4-((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol (M3)

YD: 53%. ¹H NMR (400 MHz, CDCl₃) δ8.36 (d, J=8.8 Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.18 (q, J=6.8Hz, 3H), 3.84 (s, 2H), 3.54 (t, J=5.2 Hz, 2H), 2.45-2.50 (br, 10H), 1.49(t, J=6.8 Hz, 3H); MS. m/z 350.1, [M+H]⁺.

2-(4-((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol(M4)

YD: 61%. ¹H NMR (400 MHz, d4-MeOD) δ8.52 (d, J=8.8 Hz, 1H), 7.81 (d,J=8.8 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.87 (m,1H), 3.89 (s, 2H), 3.67 (t, J=6.0 Hz, 2H), 2.54-2.62 (br, 10H), 1.45 (t,J=6.0 Hz, 6H); MS. m/z 364.1, [M+H]⁺.

2-(4-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethane(M5)

YD: 76%. ¹H NMR (400 MHz, d4-MeOD) δ8.40 (d, J=8.4 Hz, 1H), 7.71 (d,J=8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 3.97 (d,J=6.8 Hz, 2H), 3.84 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.44 (t, J=4.8 Hz,2H), 2.56 (br, 8H), 2.51 (t, J=4.8 Hz, 2H), 1.37-1.43 (m, 1H), 0.62-0.66(m, 2H), 0.37-0.40 (m, 2H); MS. m/z 376.2, [M+H]⁺.

2-(4-((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol(M6)

YD: 39%. ¹H NMR (400 MHz, d4-MeOD) δ 8.53 (d, J=8.8 Hz, 1H), 7.80 (d,J=8.8 Hz, 1H), 7.70 (s, 1H), 4.11 (s, 3H), 3.89 (s, 2H), 3.67 (t, J=6.0Hz, 2H), 2.63 (br, 8H), 2.55 (t, J=6.0 Hz, 2H), 1.93 (s, 1H); MS. m/z370.1, [M+H]⁺.

2-(4-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethanol(M7)

YD: 82%. ¹H NMR (400 MHz, CDCl₃) δ8.43 (d, J=8.8 Hz, 1H) δ7.71 (d, J=8.8Hz, 1H), 7.58 (s, 1H), 4.22 (d, J=7.2 Hz, 2H), 3.88 (s, 2H) 3.61 (t,J=6.4 Hz, 2H), 2.56 (t, J=5.2 Hz, 1.0H), 1.41-1.44 (m, 1H), 0.57-0.62(m, 2H), 0.33-0.37 (m, 2H); MS. m/z 410.1, [M+Na]⁺.

2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol (N1)

YD: 49%. ¹H NMR (400 MHz, CDCl₃) δ8.08 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 3.90 (s, 2H), 3.41 (d, J=2.0 Hz, 2H), 2.39 (s, 3H), 2.31 (d,J=2.0 Hz, 1H); MS. m/z 249.1, [M+H]⁺.

5-chloro-2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol (N2)

YD: 38%. ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.4 (d, J=8.0 Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 3.93 (s, 2H),3.42 (d, J=2.0 Hz, 2H), 2.40 (s, 3H), 2.31 (t, J=2.0 Hz, 1H); MS. m/z261.0, [M+H]⁺.

N-((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine(N3)

YD: 52%. ¹H NMR (400 MHz, CDCl₃) δ8.48 (d, J=8.8 Hz, 1H), 7.80 (d, J=8.8Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 4.05 (s, 3H),4.00 (s, 2H), 3.42 (d, J=2.0 Hz, 2H), 2.37 (s, 3H), 2.27 (t, J=2.0 Hz,1H), MS. m/z 297.0, [M+Na]⁺.

N-((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methyprop-2-yn-1-amine (N4)

YD: 64%. ¹H NMR (400 MHz, CDCl₃) δ8.48 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.32 (t, J=6.8Hz, 2H), 4.01 (s, 2H), 3.45 (d, J=2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t,J=2.0 Hz, 1H), 1.59 (t, J=6.8 Hz, 3H); MS. m/z 289.1, [M+H]⁺.

N-((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine(N5)

YD: 76%. ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=8.8 Hz, 1H), 7.73 (d, J=8.8Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 4.80 (m, 1H),3.99 (s, 2H), 3.44 (d, J=2.4 Hz, 2H), 2.41 (s, 3H), 2.28 (t, J=2.4 Hz,1H), 1.48 (d, J=6.4 Hz, 6H); MS. m/z 303.1, [M+H]⁺.

N-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine(N6)

YD: 58%. ¹H NMR (400 MHz, CDCl₃) δ8.48 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.8Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.09 (d, J=7.2Hz, 2H), 4.01 (s, 2H), 3.45 (d, J=2.0 Hz, 2H), 2.41 (s, 3H), 2.28 (t,J=2.0 Hz, 1H), 1.42˜1.50 (m, 1H), 0.65-0.70 (m, 2H), 0.42-0.45 (m, 2H);MS. m/z 337.1, [M+Na]⁺.

N-((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine(N7)

YD: 58%. ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8Hz, 1H), 7.60 (s, 1H), 4.20 (s, 3H), 3.99 (s, 2H), 3.43 (d, J=2.0 Hz,2H), 2.41 (s, 3H), 2.29 (t, J=2.0 Hz, 1H); MS. m/z 309.0, [M+H]⁺.

N-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl-N-methylprop-2-yn-1-amine(N8)

YD: 76%. ¹H NMR (400 MHz, CDCl₃) δ8.45 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.59 (s, 1H), 4.25 (d, J=7.6 Hz, 2H), 3.95 (s, 2H), 3.40 (d,J=2.0 Hz, 2H), 2.40 (s, 3H), 2.28 (t, J=2.0 Hz, 1H), 1.41-1.45 (m, 1H),0.57-0.62 (m, 2H), 0.36 (dd, J=10.0, 4.8 Hz, 2H); MS. m/z 371.0,[M+Na]⁺.

8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol (O1)

YD: 44%. ¹H NMR (400 MHz, d4-MeOD) δ8.55 (d, J=8.8 Hz, 1H), 7.69 (d,J=8.8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H) 7.16 (d, J=8.4 Hz, 1H), 4.07 (s,5H), 3.50 (t, J=6.8 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.56 (quin, J=7.2Hz, 2H), 1.50 (quin, J=6.8 Hz, 2H), 1.29-1.32 (br, 10H); MS. m/z 351.2,[M+H]⁺.

8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-1-ol (O2)

YD: 41%. ¹H NMR (400 MHz, d4-MeOD) δ8.51 (d, J=8.8 Hz, 1H), 7.66 (d,J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.29 (q,J=6.8 Hz, 2H), 4.0 (s, 2H), 3.5.1 (t, J=6.8 Hz, 2H), 2.64 (t, J=7.2 Hz,2H), 1.47-1.58 (m, 7H), 1.31 (br, 9H); MS. m/z 365.2, [M+H]⁺.

8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-1-ol (O3)

YD: 31%. ¹H NMR (400 MHz, d4-MeOD) δ8.55 (d, J=8.8 Hz, 1H), 7.66 (d,J=8.8 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 4.89 (m,1H), 4.15 (s, 2H), 3.52 (t, J=6.4 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H), 1.59(quin, J=6.8 Hz, 2H) 1.46-1.50 (m, 8H), 1.33 (br, 9H); MS. m/z 379.2,[M+H]⁺.

8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-o)(O4)

YD: 29%. ¹H NMR (400 MHz, d4-MeOD) δ8.54 (d, J=8.4 Hz, 1H), 7.67 (d,J=8.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 4.09(s+d, J=6.8 Hz, 4H), 3.51 (t, J=6.8 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H),1.59 (quin, J=7.2 Hz, 2H), 1.43-1.51 (m, 3H), 1.29-1.42 (br, 10H),0.66-0.89 (m, 2H), 0.44 (dd, J=10.4, 4.8 Hz, 2H); MS. m/z 391.2, [M+H]⁺.

8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol (O5)

YD: 37%. ¹H NMR (400 MHz, d4-MeOD) δ8.54 (d, J=8.8 Hz, 1H), 7.71 (s,1H), 7.65 (d, J=8.8 Hz, 1H), 4.14 (s, 3H), 4.12 (s, 2H), 3.52 (t, J=6.8Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.60 (quin, J=6.8 Hz, 2H), 1.50 (m,2H), 1.33 (br, 9H); MS. m/z 385.1, [M+H]⁺.

8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-ol(O6)

YD: 56%. ¹H NMR (400 MHz, d4-MeOD) δ8.51 (d, J=8.4 Hz, 1H), 7.69 (s,1H), 7.61 (d, J=8.8 Hz, 1H), 4.22 (d, J=7.2 Hz, 2H), 4.10 (s, 2H), 3.52(t, J=6.8 Hz, 2H), 2.68 (t, J=7.2 Hz, 2H), 1.59 (quin, 7.2 Hz, 2H), 1.51(quin, J=6.8 Hz, 2H), 1.28-1.42 (br, 11H), 0.55-0.60 (m, 2H), 0.30-0.33(m, 2H); MS. m/z 425.2, [M+H]⁺.

6-(bis(8-methoxyquinolin-2-yl)methyl)amino)hexan-1-ol (P1)

¹H NMR (400 MHz, d4-MeOD) δ8.18 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz,2H), 7.44 (t, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.13 (d, J=7.2 Hz,2H), 4.02 (s, 6H), 3.99 (s, 4H), 3.40 (t, J=6.8 Hz, 2H), 2.59 (t, J=6.8Hz, 2H), 1.56 (quin, J=6.8 Hz, 2H), 1.41 (quin, J=6.8 Hz, 2H), 1.27(quin, J=7.6 Hz, 2H), 1.18 (quin, J=6.8 Hz, 2H); MS. m/z 482.3, [M+Na]⁺.

FIG. 1A shows C12 inhibited Aβ aggregation in the presence or absence ofzinc ions using a microscopy analysis after Congo red staining. FIG. 1Band FIG. 2 show that C12 dissolved preformed Aβ aggregates. FIGS. 3A-Bshow that compounds C12, CQ and C12 intermediate protected neuron cellsfrom zinc-induced fAβ. Only compound C12 was effective toward zinc-freeaggregates (FIG. 3B). FIG. 4 shows induction of neurite outgrowthtriggered by compound C12 on undifferentiated PC12 cells. FIG. 5 showsquinoline derivatives increased expression of GAP43. FIG. 6 showscompound C12 and B3 improved performance of learning in fAβ-inducedmemory-deficit mice. C12 and B3 (10 mg/kg) increased riding time offAβ-lesioned mice in a rota rod test. FIGS. 7A-D show compound C12improved learning of memory-deficit fAβ-lesioned mice in the Morriswater maze test. Mice were assessed for the total duration of movement(FIG. 7A) and total duration of distance (FIG. 7B) to climb onto thehidden platform; and also quantified the appearance to target zone (FIG.7C) indicating the relative time (compared to total time in swimming) toentry into a zone around the hidden platform; and for average swimmingvelocity (FIG. 7D) to discriminate enhanced memory from enhanced motoractivity. FIG. 8 shows an increase in GAP43 level and decrease in fAβlevel in memory-deficit fAβ-lesioned mice by compound C12.

Cpd No. Chemical Name Structure Substituents Example 1 A19-(8-(benzyloxy)quinolin- 2-yl)nonan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH A2 10-(8-(benzyloxy)quinolin- 2-yl)decan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH A311-(8-(benzyloxy)quinolin- 2-yl)undecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH A412-(8-(benzyloxy)quinolin- 2-yl)dodecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH A513-(8-(benzyloxy)quinolin- 2-yl)tridecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH A614-(8-(benzyloxy)quinolin- 2-yl)tetradecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH A7 15-(8-(benzyloxy)quinolin- 2-yl)pentadecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH A811-(8-(benzyloxy)-5- methylquinolin-2- yl)undecan-1-ol

R¹ = benzyl R², R³, R⁵, and R⁶ = hydrogen R⁴ = CH₃ R⁷ = —(CH₂)₁₁OH A911-(8-(benzyloxy)-6- methylquinolin-2- yl)undecan-1-ol

R¹ = benzyl R², R⁴, R⁵, and R⁶ = hydrogen R³ = CH₃ R⁷ = —(CH₂)₁₁OH A1011-(8- (benzyloxy)-5- fluoroquinolin-2- yl)undecan-1-ol

R¹ = benzyl R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₁OH A1111-(8- (benzyloxy)-5- chloroquinolin-2- yl)undecan-1-ol

R¹ = benzyl R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OH B12-(9-hydroxynonyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH B2 2-(10-hydroxydecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH B32-(11- hydroxyundecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH B42-(12- hydroxydodecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH B52-(13- hydroxytridecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH B62-(14- hydroxytetradecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH B72-(15- hydroxypentadecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH B82-(11- hydroxyundecyl)- 5-methyl- quinolin-8-ol

R¹ = hydrogen R², R³, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH B9 2-(11-hydroxyundecyl)- 6-methyl- quinolin-8-ol

R¹ = hydrogen R², R⁴, R⁵, and R⁶ = CH₃ R⁷ = —(CH₂)₁₁OH B105-chloro-2-(11- hydroxyundecyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OHExample 2 C1 9-(8- methoxyquinolin- 2-yl)nonan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH C2 10-(8-methoxyquinolin- 2-yl)decan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH C3 11-(8-methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH C4 12-(8-methoxyquinolin- 2-yl)dodecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH C5 13-(8-methoxyquinolin- 2-yl)tridecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH C6 14-(8-methoxyquinolin- 2-yl)tetradecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH C7 15-(8-methoxyquinolin- 2-yl)pentadecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH C8 11-(8-methoxy-5- methylquinolin-2- yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = CH₃ R⁷ = —(CH₂)₁₁OH C911-(5-fluoro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₁OH C1012-(5-fluoro-8- methoxyquinolin- 2-yl)dodecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₂OH C119-(5-fluoro-8- methoxyquinolin- 2-yl)nonan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₉OH C1211-(5-chloro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OH C1315-(5-chloro-8- methoxyquinolin- 2-yl)pentadecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₅OH C1411-(5-bromo-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Br R⁷ = —(CH₂)₁₁OH C1511-(8-methoxy-5- (trifluoromethyl) quinolin-2- yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = CF₃ R⁷ = —(CH₂)₁₁OH C1611-(5,8- dimethoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = OCH₃ R⁷ = —(CH₂)₁₁OH C1711-(8-methoxy-6- methylquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁴, R⁵, and R⁶ = hydrogen R³ = CH₃ R⁷ = —(CH₂)₁₁OH C1811-(6-fluoro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁴, R⁵, and R⁶ = hydrogen R³ = F R⁷ = —(CH₂)₁₁OH C1911-(6-chloro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁴, R⁵, and R⁶ = hydrogen R³ = Cl R⁷ = —(CH₂)₁₁OH C2011-(7-fluoro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R² = F R², R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH C2111-(7-chloro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R² = Cl R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH C2211-(5-chloro-6,8- dimethoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁵, R⁶ = hydrogen R³ = OCH₃ R⁴ = Cl R⁷ = —(CH₂)₁₁OH C2311-(6-chloro-5,8- dimethoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁵, R⁶ = hydrogen R³ = Cl R⁴ = OCH₃ R⁷ = —(CH₂)₁₁OH C2411-(5,7-dichloro- 8-methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R⁴ = Cl R³, R⁵, R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH Example 3 D19-(8- ethoxyquinolin-2- yl)nonan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH D2 10-(8-ethoxyquinolin-2- yl)decan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH D3 11-(8-ethoxyquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH D4 12-(8-ethoxyquinolin-2- yl)dodecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH D5 13-(8-ethoxyquinolin-2- yl)tridecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH D6 14-(8-ethoxyquinolin-2- yl)tetradecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH D7 15-(8-ethoxyquinolin-2- yl)pentadecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH D8 11-(8-ethoxy-5- methylquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = CH₃ R⁷ = —(CH₂)₁₁OH D911-(8- ethoxy-5- fluoroquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₁OH D109-(5-chloro-8- ethoxyquinolin-2- yl)nonan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₉OH D1111-(5-chloro-8- ethoxyquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OH D1215-(5-chloro-8- ethoxyquinolin-2- yl)pentadecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₅OH D1311-(5-bromo-8- ethoxyquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Br R⁷ = —(CH₂)₁₁OH D1411-(5,7-dichloro-8- ethoxyquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH₃ R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH E19-(8- isopropoxyquinolin- 2-yl)nonan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH E2 10-(8-isopropoxyquinolin- 2-yl)decan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH E311-(8- isopropoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH E412-(8- isopropoxyquinolin- 2-yl)dodecan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH E513-(8- isopropoxyquinolin- 2-yl)tridecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH E614-(8- isopropoxyquinolin- 2-yl)tetradecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH E715-(8- isopropoxyquinolin- 2-yl)pentadecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH E811-(8-isopropoxy- 5-methylquinolin- 2-yl)undecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = CH₃ R⁷ = —(CH₂)₁₁OHE9 11-(5-fluoro-8- isopropoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₁OHE10 9-(5-chloro-8- isopropoxyquinolin- 2-yl)nonan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₉OHE11 11-(5-chloro-8- isopropoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OHE12 15-(5-chloro-8- isopropoxyquinolin- 2-yl)pentadecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₅OHE13 11-(5-bromo-8- isopropoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Br R⁷ = —(CH₂)₁₁OHE14 11-(5,7-dichloro-8- isopropoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₂CH(CH₃)₂ R², R⁴ = Cl R³, R⁵, R⁶ = hydrogen R⁷ = —(CH₂)₁₁OHExample 4 F1 9-(8-(cyclopropyl- methoxy)quinolin-2- yl)nonan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH F210-(8-(cyclopropyl- methoxy)quinolin-2- yl)decan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₀OH F111-(8-(cyclopropyl- methoxy)quinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH F412-(8-(cyclopropyl- methoxy)quinolin-2- yl)dodecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₂OH F513-(8-(cyclopropyl- methoxy)quinolin-2- yl)tridecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₃OH F614-(8-(cyclopropyl- methoxy)quinolin-2- yl)tetradecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH F715-(8-(cyclopropyl- methoxy)quinolin-2- yl)pentadecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH F811-(8-(cyclopropyl- methoxy)-5- methylquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = CH₃ R⁷ = —(CH₂)₁₁OHF9 11-(8-(cyclopropyl- methoxy)-5- fluoroquinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₁₁OHF10 9-(5-chloro-8- (cyclopropylmethoxy) quinolin-2- yl)nonan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = F R⁷ = —(CH₂)₉OH F1111-(5-chloro-8- (cyclopropylmethoxy) quinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OHF12 15-(5-chloro-8- (cyclopropylmethoxy) quinolin-2- yl)pentadecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₅OHF13 11-(5-bromo-8- (cyclopropylmethoxy) quinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Br R⁷ = —(CH₂)₁₁OHF14 11-(5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OHExample 5 G1 5,7-dichloro-2- (11-hydroxyundecyl) quinolin-8-ol

R¹ = hydrogen R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OHExample 6 H1A 10-(5-Chloro-8- methoxyquinolin- 2-yl)decan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₀OH H1Bacetic acid 10-(5- chloro-8- methoxyquinolin- 2-yl)decyl ester

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = (CH₂)₁₀OCOCH₃ H2A11-(5-Chloro-8- methoxyquinolin- 2-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₁OH H2Bacetic acid 11-(5- chloro-8- methoxyquinolin- 2-yl)undecyl ester

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = (CH₂)₁₁OCOCH₃ H3A12-(5-Chloro-8- methoxyquinolin- 2-yl)dodecan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₂OH H3Bacetic acid 12-(5- chloro-8- methoxyquinolin- 2-yl)dodecyl ester

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₂OCOCH₃ H4A13-(5-Chloro-8- methoxyquinolin- 2-yl)decan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₃OH H4Bacetic acid 13-(5- chloro-8- methoxyquinolin- 2-yl)tridecyl ester

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —(CH₂)₁₀OCOCH₃Example 7 I1 11-(8- methoxyquinolin- 4-yl)undecan-1-ol

R¹ = CH₃ R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I2 11-(8-ethoxyquinolin- 4-yl)undecan-1-ol

R¹ = CH₂CH₃ R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I3 11-(8-isopropoxyquinolin- 4-yl)undecan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I411-(8- (cyclopropylmethoxy) quinolin-4- yl)undecan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I511-(8- (benzyloxy)quinolin- 4-yl)undecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I6 12-(8-(benzyloxy)quinolin- 4-yl)dodecan-1-ol

R¹ = benzyl R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₂OH I7 4-(11-hydroxyundecyl) quinolin-1-ol

R¹ = hydrogen R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₁OH I84-(12- hydroxyundecyl) quinolin-1-ol

R¹ = hydrogen R², R³, R⁴, R⁶, and R⁷ = hydrogen R⁵ = —(CH₂)₁₂OH Example8 L1 9-(8- (trifluoromethoxy) quinolin-2- yl)nona-1-ol

R¹ = CF₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₉OH L2 11-(8-(trifluoromethoxy) quinolin-2- yl)undecan-1-ol

R¹ = CF₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₁OH L3 14-(8-(trifluoromethoxy) quinolin-2- yl)tetradecan-1-ol

R¹ = CF₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₄OH L4 15-(8-(trifluoromethoxy) quinolin-2- yl)pentadecan-1-ol

R¹ = CF₃ R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —(CH₂)₁₅OH Example 9 M12-((4-(2- hydroxyethyl) piperazin-1-yl)methyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH M2 2-(4-((5-chloro-8- methoxyquinolin-2-yl)methyl)piperazin-1- yl)ethanol

R¹ = hydrogen R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH M3 2-(4-((5-chloro-8- ethoxyquinolin-2-yl)methyl)piperazin-1- yl)ethanol

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH M4 2-(4-((5-chloro-8- isopropoxyquinolin-2-yl)methyl)piperazin-1- yl)ethanol

R¹ = CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH M5 2-(4-((5-chloro-8- (cyclopropylmethyoxy)quinolin-2- yl)methyl)piperazin-1- yl)ethanol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₃ M6 2-(4-((5,7-dichloro-8- methoxyquinolin-2-yl)methyl)piperazin- 1-yl)ethanol

R¹ = CH₃ R², R⁴ = Cl R³, R⁵, R⁶ = hydrogen R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH M7 2-(4-((5,7-dichloro-8-(cyclopropylmethoxy) quinolin-2- yl)methyl)piperazin- 1-yl)ethanol

R¹ = CH₂CH(CH₂)₂ R², R⁴ = Cl R³, R⁵, R⁶ = hydrogen R⁷ =—CH₂—(N(CH₂CH₂)₂N)CH₂CH₂OH N1 2-((methyl(prop-2- ynyl)amino)methyl)quinolin-8-ol

R¹ = hydrogen R², R³, R⁴, R⁵, and R⁶ = hydrogen R⁷ = —CH₂N(CH₃)CH₂C≡CHN2 5-chloro-2- ((methyl(prop-2- ynyl)amino)methyl) quinolin-8-ol

R¹ = hydrogen R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂N(CH₃)CH₂C≡CH N3 N-((5-chloro-8- methoxyquinolin- 2-yl)methyl)-N-methylprop-2-yn-1-amine

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —CH₂N(CH₃)CH₂C≡CH N4N-((5-chloro-8- ethoxyquinolin- 2-yl)methyl)-N- methylprop-2-yn-1-amine

R¹ = CH₂CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = —CH₂N(CH₃)CH₂C≡CHN5 N-((5-chloro-8- isopropoxyquinolin- 2-yl)methyl)-N- methylprop-2-yn-1-amine

R¹ = CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂N(CH₃)CH₂C≡CH N6 N-((5-chloro-8- (cyclopropylmethoxy)quinolin-2-yl)methyl)-N- methylprop-2-yn- 1-amine

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =—CH₂N(CH₃)CH₂C≡CH N7 N-((5,7-dichloro-8- methoxyquinolin-2-yl)methyl)-N- methylprop-2-yn- 1-amine

R¹ = CH₃ R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ = —CH₂N(CH₃)CH₂C≡CH N8N-((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2-yl)methyl)-N-methylprop-2-yn- 1-amine

R¹ = CH(CH₂)₂ R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ =—CH₂N(CH₃)CH₂C≡CH O1 8-((5-chloro-8- methoxyquinolin- 2-yl)methylamino)octan-1-ol

R¹ = CH₃ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = CH₂NH(CH₂)₈OH O28-((5-chloro-8- ethoxyquinolin-2- yl)methylamino) octan-1-ol

R¹ = CH₂CH3 R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = CH₂NH(CH₂)₈OH O38-((5-chloro-8- isopropoxyquinolin-2- yl)methylamino) octan-1-ol

R¹ = CH(CH₃)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ = CH₂NH(CH₂)₈OHO4 8-((5-chloro-8- (cyclopropylmethoxy) quinolin-2- yl)methylamino)octan-1-ol

R¹ = CH₂CH(CH₂)₂ R², R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =CH₂NH(CH₂)₈OH O5 8-((5,7-dichloro-8- methoxyquinolin-2- yl)methylamino)octan-1-ol

R¹ = CH₃ R², R⁴ = Cl R³, R⁵, and R⁶ = hydrogen R⁷ = CH₂NH(CH₂)₈OH O68-((5,7-dichloro-8- (cyclopropylmethoxy) quinolin-2- yl)methylamino)octan-1-ol

R¹ = CH₂CH(CH₂)₂ R² = Cl R³, R⁵, and R⁶ = hydrogen R⁴ = Cl R⁷ =CH₂NH(CH₂)₈OH P1 6-(bis((8- methoxyquinolin-2- yl)methyl)amino)hexan-1-ol

R¹ = CH₃ R², R₄, R³, R⁵, and R⁶ = hydrogen R⁷ = CH₂N((CH₂)₆OH)CH₂(8-methoxyquinolin-2-yl)

The foregoing description of the exemplary embodiments of the inventionhas been presented only for the purposes of illustration and descriptionand is not intended to be exhaustive or to limit the invention to theprecise forms disclosed. Many modifications and variations are possiblein light of the above teaching.

The embodiments and examples were chosen and described in order toexplain the principles of the invention and their practical applicationso as to enable others skilled in the art to utilize the invention andvarious embodiments and with various modifications as are suited to theparticular use contemplated. Alternative embodiments will becomeapparent to those skilled in the art to which the present inventionpertains without departing from its spirit and scope. Accordingly, thescope of the present invention is defined by the appended claims ratherthan the foregoing description and the exemplary embodiments describedtherein.

Some references, which may include patents, patent applications andvarious publications, are cited and discussed in the description of thisinvention. The citation and/or discussion of such references is providedmerely to clarify the description of the present invention and is not anadmission that any such reference is “prior art” to the inventiondescribed herein. All references cited and discussed in thisspecification are incorporated herein by reference in their entiretiesand to the same extent as if each reference was individuallyincorporated by reference.

What is claimed is:
 1. A compound of Formula (I) or a pharmaceuticallyacceptable salt, a solvate or hydrate, a prodrug, or a metabolitethereof:

wherein R¹ is hydrogen, (C₁-C₈)alkyl, (C₁-C₈)alkylene(C₃-C₈)cycloalkyl,(C₁-C₈)haloalkyl, or (C₁-C₈)alkylene(C₆-C₂₀)aryl; R² is hydrogen orhalogen; R³is hydrogen, halogen, (C₁-C₈)alkyl, or (C₁-C₈)alkoxy; R⁴ ishydrogen, halogen, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, or (C₁-C₈)haloalkyl; R⁵is hydrogen or (C₁-C₂₀)alkanol; R⁶ is hydrogen; and R⁷ is hydrogen,(C₁-C₂₀)alkanol, (C₁-C₈)alkylene (C₃-C₈)heterocyclyl(C₁-C₂₀)alkanol,(C₁-C₈)alkylene (C₃-C₈)heterocyclyl(C₁-C₂₀)alkyl,(C₁-C₈)alkylene(C₁-C₆)alkylamino(C₁-C₆)alkynyl,(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol, or(C₁-C₈)alkyleneamino(C₁-C₂₀)alkanol(C₁-C₈)alkylene substituted(C₃-C₂₀)heteroaryl.
 2. The compound of claim 1, wherein R¹is hydrogen,CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CF₃, or benzyl; R² is hydrogen, F,or Cl; R³ is hydrogen, F, Cl, CH₃, or OCH₃; R⁴ is hydrogen, F, Cl, Br,CH₃, OCH₃, or CF₃; R⁵ is hydrogen, (CH₂)₁₁OH, or (CH₂)₁₂OH; R⁶ ishydrogen; and R⁷ is hydrogen, (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH,(CH₂)₁₃OH, (CH₂)₁₄OH, (CH₂)₁₅OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH,CH₂(N(CH₂CH₂)₂N)CH₂CH₃, CH₂N(CH₃)CH₂C≡CH, CH₂NH(CH₂)₈OH, orCH₂N((CH₂)₆OH)CH₂(8-methoxyquinolin-2-yl).
 3. The compound of claim 2,wherein R¹ is hydrogen, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂,CF₃, or benzyl; R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen;and R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH,(CH₂)₁₄OH, (CH₂)₁₅OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH, or CH₂N(CH₃)CH₂C≡CH. 4.The compound of claim 2, wherein R¹ is hydrogen, CH₃, CH₂CH₃,CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂; R², R³, R⁵, and R⁶ are eachindependently hydrogen; R⁴ is CH₃, F, Cl, Br, CF₃ or OCH₃; and R⁷ is(CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH,(CH₂)₁₀OCOCH₃, (CH₂)₁₁OCOCH₃, (CH₂)₁₂OCOCH₃, (CH₂)₁₃OCOCH₃,CH₂NH(CH₂)₈OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₂OH, CH₂(N(CH₂CH₂)₂N)CH₂CH₃, orCH₂N(CH₃)CH₂C≡CH.
 5. The compound of claim 2, wherein R¹ is hydrogen,CH₃, CH₂CH₃, CH(CH₂)₂, or CH₂CH(CH₂)₂; R², R⁴ are each independently Cl;R³, R⁵, and R⁶ are each independently hydrogen; and R⁷ is (CH₂)₁₁OH,CH₂NH(CH₂)₈OH, or CH₂N(CH₃)CH₂≡CH.
 6. The compound of claim 2, whereinR¹ is hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, CH(CH₃)₂, orbenzyl; R², R³, R⁴, R⁶, and R⁷ are each independently hydrogen; and R⁵is (CH₂)₁₁OH or (CH₂)₁₂OH.
 7. The compound of claim 2, wherein R¹ isCH₃; R², R⁵, and R⁶ are each independently hydrogen; R³ and R4 are eachindependently OCH₃ or Cl; and R⁷ is (CH₂)₁₁OH.
 8. The compound of claim2, which is selected from the group consisting of:9-(8-(benzyloxy)quinolin-2-yl)nonan-1-ol,10-(8-(benzyloxy)quinolin-2-yl)decan-1-ol,11-(8-(benzyloxy)qninolin-2-yl)undecan-1-ol,12-(8-(benzyloxy)quinolin-2-yl)dodecan-1-ol,13-(8-(benzyloxy)quinolin-2-yl)tridecan-1-ol,14-((8-(benzyloxy)quinolin-2-yl)tetradecan-1-ol,15-(8-(benzyloxy)quinolin-2-yl)pentadecan-1-ol,11-(8-(benzyloxy)-5-methylquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-6-methylquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-5-fluoroquinolin-2-yl)undecan-1-ol,11-(8-(benzyloxy)-5-chloroquinolin-2-yl)undecan-1-ol,2-(9-hydroxynonyl)quinolin-8-ol, 2-(10-hydroxydecyl)quinolin-8-ol,2-(11-hydroxyundecyl)quinolin-8-ol, 2-(12-hydroxydodecyl)quinolin-8-ol,2-(13-hydroxytridecyl)quinolin-8-ol,2-(14-(-hydroxytetradecyl)quinolin-8-ol,2-(15-hydroxypentadecyl)quinolin-8-ol,2-(11-hydroxyundecyl)-5-methylquinolin-8-ol,2-(11-hydroxyundecyl)-6-methylquinolin-8-ol,5-chloro-2-(11-hydroxyundecyl)quinolin-8-ol,9-(8-methoxyquinolin-2-yl)nonan-1-ol,10-(8-methoxyquinolin-2-yl)decan-1-ol,11-(8-methoxyquinolin-2-yl)undecan-1-ol,12-(8-methoxyquinolin-2-yl)dodecan-1-ol,13-(8-methoxyquinolin-2-yl)tridecan-1-ol,14-((8-methoxyquinolin-2-yl)tetradecan-1-ol,15-(8-methoxyquinolin-2-yl)pentadecan-1-ol,11-(8-methoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(5-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,12-(5-fluoro-8-methoxyquinolin-2-yl)dodecan-1-ol,9-(5-chloro-8-methoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-methoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-methoxyquinolin-2-yl)undecan-1-ol,11-(8-methoxy-5-(trifluoromethyl)quinolin-2-yl)undecan-1-ol,11-(5,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(8-methoxy-6-methylquinolin-2-yl)undecan-1-ol,11-(6-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(6-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(7-fluoro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(7-chloro-8-methoxyquinolin-2-yl)undecan-1-ol,11-(5-chloro-6,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(6-chloro-5,8-dimethoxyquinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-methoxyquinolin-2-yl)undecan-1-ol,9-(8-ethoxyquinolin-2-yl)nonan-1-ol,10-(8-ethoxyquinolin-2-yl)decan-1-ol,11-(8-ethoxyquinolin-2-yl)undecan-1-ol,12-(8-ethoxyquinolin-2-yl)dodecan-1-ol,13-(8-ethoxyquinolin-2-yl)tridecan-1-ol,14-((8-ethoxyquinolin-2-yl)tetradecan-1-ol,15-(8-ethoxyquinolin-2-yl)pentadecan-1-ol,11-(8-ethoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(8-ethoxy-5-fluoroquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-ethoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-ethoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-ethoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-ethoxyquinolin-2-yl)undecan-1-ol;11-(5,7-dichloro-8-ethoxyquinolin-2-yl)undecan-1-ol,9-(8-isopropoxyquinolin-2-yl)nonan-1-ol,10-(8-isopropoxyquinolin-2-yl)decan-1-ol,11-(8-isopropoxyquinolin-2-yl)undecan-1-ol,12-(8-isopropoxyquinolin-2-yl)dodecan-1-ol,13-(8-isopropoxyquinolin-2-yl)tridecan-1-ol,14-((8-isopropoxyquinolin-2-yl)tetradecan-1-ol,15-(8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(8-isopropoxy-5-methylquinolin-2-yl)undecan-1-ol,11-(5-fluoro-8-isopropoxyquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-isopropoxyquinolin-2-yl)nonan-1-ol,11-(5-chloro-8-isopropoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-1-ol,15-(5-chloro-8-isopropoxyquinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-isopropoxyquinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-isopropoxyquinolin-2-yl)undecan-1-ol,9-(8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol,10-(8-(cyclopropylmethoxy)quinolin-2-yl)decan-1-ol,11-(8-cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,12-(8-(cyclopropylmethoxy)quinolin-2-yl)dodecan-1-ol,13-(8-cyclopropylmethoxy)quinolin-2-yl)tridecan-1-ol,14-((8-(cyclopropylmethoxy)quinolin-2-yl)tetradecan-1-ol,15-(8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol,11-(8-(cyclopropylmethoxy)-5-methylquinolin-2-yl)undecan-1-ol,11-(8-(cyclopropylmethoxy)-5-fluoroquinolin-2-yl)undecan-1-ol,9-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)nonan-1-ol,11-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,15-(5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)pentadecan-1-ol,11-(5-bromo-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,11-(5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)undecan-1-ol,5,7-dichloro-2-(11-hydroxyundecyl)quinolin-8-ol,10-(5-chloro-8-methoxyquinolin-2-yl)decan-1-ol, acetic acid10-(5-chloro-8-methoxyquinolin-2-yl)decyl ester,11-(5-chloro-8-methoxyquinolin-2-yl)undecan-1-ol, acetic acid11-(5-chloro-8-methoxyquinolin-2-yl)undecyl ester,12-(5-chloro-8-methoxyquinolin-2-yl)dodecan-1-ol, acetic acid12-(5-chloro-8-methoxyquinolin-2-yl)dodecyl ester,13-(5-(chloro-8-methoxyquinolin-2-yl)tridecan-1-ol, acetic acid13-(5-chloro-8-methoxyquinolin-2-yl)tridecyl ester,11-(8-methoxyquinolin-4-(-yl)undecan-1-ol,11-(8-ethoxyquinolin-4-(-yl)undecan-1-ol,11-(8-isopropoxyquinolin-4-(-yl)undecan-1-ol,11-(8-(cyclopropylmethoxy)quinolin-4-(-yl)undecan-1-ol,11-(8-benzyloxy)quinolin-4-(-yl)undecan-1-ol,12-(8-benzyloxy)quinolin-4-(-yl)dodecan-1-ol,4-((11-hydroxyundecyl)quinolin-8-ol,4-((12-hydroxydodecyl)quinolin-8-ol,9-(8-trifluoromethoxy)quinolin-2-yl)nona-1-ol,11-(8-(trifluoromethoxy)quinolin-2-yl)undecan-1-ol,14-((8-(trifluoromethoxy)quinolin-2-yl)tetradecan-1-ol,15-(8-(trifluoromethoxy)quinolin-2-yl)pentadecan-1-ol,2-((4-((2-hydroxyethyl)piperazin-1-yl)methyl)quinolin-8-ol,2-(4-(((5-chloro-8-methoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-(4-(((5-chloro-8-ethoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-(4-(((5-chloro-8-isopropoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-(4-(((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethane,2-(4-(((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-(4-(((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)piperazin-1-yl)ethanol,2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol,5-chloro-2-((methyl(prop-2-ynyl)amino)methyl)quinolin-8-ol,N((5-chloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5-chloro-8-ethoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5-chloro-8-isopropoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5,7-dichloro-8-methoxyquinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,N((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methyl)-N-methylprop-2-yn-1-amine,8-((5-chloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-ethoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-isopropoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5-chloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-ol,8-((5,7-dichloro-8-methoxyquinolin-2-yl)methylamino)octan-1-ol,8-((5,7-dichloro-8-(cyclopropylmethoxy)quinolin-2-yl)methylamino)octan-1-ol,and 6-(bis((8-methoxyquinolin-2-yl)methyl)amino)hexan-1-ol.
 9. A methodfor preparing the compound of claim 1, comprising: (15) reacting thecompound of Formula (II)

wherein: R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or R²,R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or R², R³,R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F, Cl, or Br;or R², R⁵, R⁶ are each independently hydrogen, R³ OCH₃, and R⁴ is Cl; orR², R⁴ is Cl and R³, R⁵, R⁶ are each independently hydrogen, with benzylbromide, methyl iodide, ethyl iodide, 2-bromopropane, ormethylenecyclopropyl bromide in a basic solution at about roomtemperature to about 80° C. to obtain the compound of Formula (III)

wherein: R¹ is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or benzyl; and R²,R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or R², R⁴, R⁵, andR⁶ are each independently hydrogen and R³ is CH₃; or R², R³, R⁵and R⁶are each independently hydrogen and R⁴ is CH₃, F, Cl, or Br; or R², R⁵,R⁶ are each independently hydrogen, R³ is OCH₃, and R⁴ is Cl; or R², R⁴is Cl and R³, R⁵, R⁶ are each independently hydrogen; (16) reacting thecompound of Formula (III) with lithium bis(trimethylsilyl)amide and abromo(C₁-C₂₀)alkanol in tetrahydrofuran at 0° C. to obtain the compoundof Formula (I)

wherein: R¹ is CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or benzyl; R², R³,R⁴, R⁵, and R⁶ are each independently hydrogen; or R², R⁴, R⁵, and R⁶are each independently hydrogen and R³ is CH₃; or R², R³, R⁵, and R⁶ areeach independently hydrogen and R⁴ is CH₃, F, Cl, or Br; or R², R⁵, R⁶are each independently hydrogen, R³ is OCH₃, and R⁴ is Cl; or R³ is Cland R⁴ is OCH₃ or R², R⁴ is Cl and R³, R⁵, R⁶ are each independentlyhydrogen; and R⁷ is (CH₂)₉OH, (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH,(CH₂)₁₃OH, (CH₂)₁₅OH, (17) reacting the compound of Formula (I), whereinR¹ is benzyl, with hydrogen gas under pressure with palladium on carbonat room temperature in methanol or with boron trichloride indichloromethane at 0° C. to obtain the compound of Formula (I)

R¹, R², R³, R⁴, R⁵, and R⁶ are each independently hydrogen; or R¹, R²,R⁴, R⁵, and R⁶ are each independently hydrogen and R³ is CH₃; or R¹, R²,R³, R⁵, and R⁶ are each independently hydrogen and R⁴ is CH₃, F, Cl, orBr; or R¹, R², R⁵, R⁶ are each independently hydrogen, R³ is OCH₃, andR⁴ is Cl; R³ is Cl, and R⁴ is OCH₃; or R², R⁴ is Cl and R¹, R³, R⁵, R⁶are each independently hydrogen; and R⁷ is (CH₂)₉OH, (CH₂)₁₀OH,(CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH; or (18) reacting thecompound of Formula (I), wherein R¹, R², R³, R⁴, R⁵ , and R⁶ are eachindependently hydrogen and R⁷ is (CH₂)₁₁OH, with N-chlorosuccinimide inmethyl chloride at room temperature to afford the compound of Formula(I), wherein R¹, R³, R⁵, and R⁶ are each independently hydrogen, R² andR⁴ are each independently chlorine, and R⁷ is (CH₂)₁₁OH; or (19)reacting the compound of Formula (I), wherein R¹ is methyl R², R³, R⁴,R⁵, and R⁶ are each independently hydrogen and R⁷ is (CH₂)₁₁OH,(CH₂)₁₂OH or (CH₂)₁₃OH with concentrated hydrochloric acid, ICl₃, andglacial acetic acid to afford the compound of Formula (I), wherein R¹ ismethyl, R², R³, R⁵, and R⁶ are each independently hydrogen, R⁴ is Cl,and R⁷ is (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₃OH, (CH₂)₁₅OH,(CH₂)₁₀OCOCH₃, (CH₂)₁₁OCOCH₃, (CH₂)₁₂OCOCH₃, (CH₂)₁₃OCOCH₃; or (20)reacting 2-aminophenol with methylvinyl ketone in hydrochloric acid toobtain the compound of Formula (INT-1)

(21) reacting the compound of Formula (INT-1) with methyl iodide, ethyliodide, 2-bromopropane, methylenecyclopropyl bromide, or benzyl bromidein basic solution to afford the compound of Formula (III),

wherein R¹⁰ is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl;(22) reacting the compound of Formula (III), wherein R¹⁰ is methyl,ethyl, 2-propyl, methylenecyclopropyl, or benzyl, with lithiumbis(trimethylsilyl)amide and 11-bromo-undecanol or 12-bromododecanol intetrahydrofuran at 0° C. to obtain the compound of Formula (I), whereinR¹ is methyl, ethyl, 2-propyl, methylenecyclopropyl, or benzyl; R², R³,R⁴, R⁶, and R⁷ are each independently hydrogen; and R⁵ is (CH₂)₁₁OH or(CH₂)₁₂OH; (23) reacting the compound of Formula (I), wherein R¹ isbenzyl; R², R³, R⁴, R⁶, and R⁷ are each independently hydrogen; and R⁵is (CH₂)₁₁OH or (CH₂)₁₂OH, with hydrogen gas under pressure withpalladium on carbon at room temperature in methanol to obtain thecompound of Formula (I), wherein R¹ is hydrogen; R², R³, R⁴, R⁶, and R⁷are each independently hydrogen; and R⁵ is (CH₂)₁₁OH or (CH₂)₁₂OH; or(24) reacting 2-trifluoromethoxyanaline with crotonaldehyde to obtain2-methyl-8-trifluormethoxyquinoline, which is treated with lithiumbis(trimethylsilyl)amide and a bromo(C₁C₂₀)alkanol in tetrahydrofuran at0° C. to obtain the compound of Formula (I), wherein R¹ istrifluoroemethyl; R², R³, R⁴, R⁵, and R⁷ are each independentlyhydrogen; and R⁷ is (CH₂)₁₀OH, (CH₂)₁₁OH, (CH₂)₁₂OH, (CH₂)₁₅OH,or(CH₂)₁₅OH; or (25) reacting an 8-hydroxy-2-methylquinoline compound ofFormula (IV), wherein R¹ is hydrogen, methyl, ethyl, 2-propyl, ormethylenecyclopropyl,

with selenium dioxide in dioxane at elevated temperature to afford acompound of Formula (VI), R¹ is hydrogen, methyl, ethyl, 2-propyl, ormethylenecyclopropyl.

(26) reacting the compound of Formula (VI), wherein R¹ is hydrogen,methyl, ethyl, 2-propyl, or methylenecyclopropyl, withN-methylpropagylamine to obtain a compound of Formula (I), wherein R¹ ishydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂, R², R³,R⁴, R⁵, and R⁶ are each independently hydrogen; and R⁷ isCH₂N(CH₃)CH₂C≡CH; or (27) reacting the compound of Formula (VI), R¹ ishydrogen, methyl, ethyl, 2-propyl, or methylenecyclopropyl, with2(piperazin-1-yl) ethanol to obtain a compound of Formula (I), whereinR¹ is hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂, R²,R³, R⁴, R⁵, and R⁶ are each independently hydrogen; and R⁷ isCH₂(N(CH₂CH₂)₂N)CH₂CH₂OH; or (28) reacting compound of Formula (VI) withan amino(C₁-C₂₀)alkanol to obtain a compound of Formula (I), wherein R¹is hydrogen, CH₃, CH₂CH₃, CH₂CH(CH₃)₂, CH₂CH(CH₂)₂, or CH(CH₃)₂; R², R³,R⁴, R⁵, and R⁶ are each independently hydrogen; and R⁷ is CH₂NH(CH₂)₈OH,or (CH₂N((CH₂)₆OH)CH₂(8-methoxyquinolin-2-yl).
 10. A compositioncomprising a therapeutically effective amount of the compound of claim1, or a pharmaceutically acceptable salt, a solvate or hydrate, aprodrug, or a metabolite thereof, and a pharmaceutically acceptablevehicle or carrier.
 11. A method for treating a neurodegenerativedisease, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or ametabolite thereof, and a pharmaceutically acceptable vehicle orcarrier.
 12. The method of claim 11, wherein the neurodegenerativedisease is selected from the group consisting of Alzheimer s disease,amylotrophic lateral sclerosis (ALS), cognitive disorder, cerebralischaemia stroke, cerebral palsy, stroke, haemorrhagic stroke,Creutzfeldt-Jacob disease, spongiform encephalopathy, Mad Cow disease,dementia, depression, Down's syndrome, epilepsy, frontotemporaldementia, Gilles de la Tourette's syndrome, Hallerboden-Spatz disease,Huntington's disease, Lewy body disease, Parkinson's disease, cognitiveimpairment, Seaming deficit, macular degeneration, memory deficit,multiple sclerosis, multiple system atrophy, motor neuron disease,Pick's disease, progressive supranuclear palsy, pseudo dementia,retinopathy, senile dementia, schizophrenia transient anoxial inducedneurodegeneration, brain traumatic injury, and spinal cord injury.
 13. Amethod for treating a neurodegenerative disease, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the compound of claim 2 or a pharmaceutically acceptable salt,a solvate or hydrate, a prodrug, or a metabolite thereof and apharmaceutically acceptable vehicle or carrier.
 14. A method fortreating a neurodegenerative disease, comprising administering to asubject in need thereof a therapeutically effective amount of thecompound of claim 3 or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof and a pharmaceuticallyacceptable vehicle or carrier.
 15. A method for treating aneurodegenerative disease, comprising administering to a subject in needthereof a therapeutically effective amount of the compound of claim 4 ora pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, ora metabolite thereof, and a pharmaceutically acceptable vehicle orcarrier.
 16. A method for treating a neurodegenerative disease,comprising administering to a subject in need thereof a therapeuticallyeffective amount of the compound of claim 5 or a pharmaceuticallyacceptable salt, a solvate or hydrate, a prodrug, or a metabolitethereof and a pharmaceutically acceptable vehicle or carrier.
 17. Amethod for treating a neurodegenerative disease, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the compound of claim 6 or a pharmaceutically acceptable salt,a solvate or hydrate, a prodrug, or a metabolite thereof, and apharmaceutically acceptable vehicle or carrier.
 18. A method fortreating a neurodegenerative disease, comprising administering to asubject in need thereof a therapeutically effective amount of thecompound of claim 7 or a pharmaceutically acceptable salt, a solvate orhydrate, a prodrug, or a metabolite thereof, and a pharmaceuticallyacceptable vehicle or carrier.
 19. A method for treating aneurodegenerative disease, comprising administering to a subject in needthereof a therapeutically effective amount of the compound of claim 8 ora pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, ora metabolite thereof, and a pharmaceutically acceptable vehicle orcarrier.
 20. The method of claim 19, wherein the neurodegenerativedisease is selected from the group consisting of Alzheimer's disease,amyotrophic lateral sclerosis (ALS), cognitive disorder, cerebralischaemia stroke, cerebral palsy, stroke, hemorrhagic stroke,Creutzfeldt-Jacob disease, spongiform encephalopathy, Mad Cow disease,dementia, depression, Down's syndrome, epilepsy, frontotemporaldementia, Gilles de la Tourette's syndrome, Hallerboden-Spatz disease,Huntington's disease, Lewy body disease, Parkinson's disease, cognitiveimpairment, learning deficit, macular degeneration, memory deficit,multiple sclerosis, multiple system atrophy, motor neuron disease,Pick's disease, progressive supranuclear palsy, pseudo dementia,retinopathy, senile dementia, schizophrenia transient anoxial inducedneurodegeneration, brain traumatic injury, and spinal cord injury.